PATENT ABSTRACT
The invention discloses a catalog of targets of the myc oncogene family identified by Serial Analysis of Gene Expression. The invention also discloses a method for analyzing myc downstream targets in view of the full context of myc induced changes in gene expression. The invention further discloses a method for the treatment of cancer comprising modulating a myc-dependent downstream gene capable of supporting an essentially neoplastic characteristic of the cancer. The invention additionally discloses a method of screening to identify drugs that interfere with myc downstream effects.

PATENT DESCRIPTION
CROSS-REFERENCE TO RELATED APPLICATIONS  
       [0001]    This application is a continuation of PCT/NL01/00361, filed May 11, 2001, designating the United States of America, corresponding to WO 01/85941 (published Nov. 15, 2001), the contents of which are incorporated herein in its entirety. 
     
    
     
       TECHNICAL FIELD  
         [0002]    The invention relates to the treatment and diagnosis of cancer and to the development of drugs for the treatment of cancer.  
         BACKGROUND  
         [0003]    The normal healthy organism maintains a carefully regulated balance that responds to specific needs of the body. In particular, the balance between the creation or multiplication of new cells and the death of superfluous cells is well maintained. However, the exquisite controls that regulate cell multiplication occasionally break down and a cell will grow and divide although the body has no further need for cells of its type. The cell essentially becomes neoplastic whereas there is no real need for the cell. When the descendants of such a cell inherit the propensity to multiply without regulation, the result is a clone of cells that are able to expand indefinitely. Ultimately, a mass called a tumor may be formed by the clones of unwanted cells and the affected individual may develop the beginning of cancer.  
           [0004]    In older individuals, neoplasias or tumors arise with great frequency, but often pose little risk to the host in which the tumor is located because the tumor is localized and generally called benign. Tumors may become life-threatening if the tumor spreads through the body. Such tumors are often called malignant and are a further development of cancer.  
           [0005]    The major characteristics that differentiate malignant tumors from benign tumors are the invasiveness and spread of the malignant tumor. Malignant tumors do not remain localized and encapsulated, but instead the malignant tumors may invade surrounding tissues, get into the body&#39;s circulatory system, and proliferate in areas away from the site of the malignant tumor&#39;s original appearance. The spread of malignant tumor cells and establishment of secondary areas of growth is called metastasis, wherein the multiplying and spreading malignant cells have acquired the ability to metastasize.  
           [0006]    Since apparently benign tumors may progress to malignancy and early stages of malignant tumors are hard to identify, pathologists are rarely sure how malignancies begin. The cells of malignant tumors have a tendency to lose differentiated traits, to acquire altered chromosomal compositions, and to become essentially metastatic where the malignant cells become invasive and spread.  
           [0007]    A wealth of knowledge has been developed about the genetic events that transform a normally regulated cell into a cell that grows without responding to controls. The genetic events are generally not inherited through the gametes, but rather are changes in the DNA of somatic cells. The principal type of change is the alteration of pre-existing genes into oncogenes, whose products cause the inappropriate cell growth. Thus, DNA alteration is at the heart of cancer induction and much focus has been given in scientific research to elucidating the causative genetic events. For example, the members of the myc oncogene family play an important role in cancer. In response to the frequency of genetic alterations of myc genes in human cancers (Dang and Lee, 1995), it is estimated that there are approximately 70,000 cancer deaths in the United States per year which are associated with changes in myc genes or in their expression. Three members of the myc-family, N-myc, c-myc and L-myc are rearranged, amplified, mutated and/or over-expressed in many cancers of the lung, breast colon, in various leukemias and brain tumors.  
           [0008]    The c-myc gene is expressed in a wide variety of tissues and tumors, while N-myc expression is largely restricted to embryonic tissues, pre-B cells and neuroendocrine tumors. N-myc is amplified in human neuroblastoma, small cell lung carcinoma and strongly expressed in Wilms&#39; tumors and retinoblastoma. Neuroblastoma is a childhood tumor with a highly variable prognosis. Approximately 20% of neuroblastomas have N-myc amplification and the tumors follow a very aggressive course (Schwab et al., 1983, Seeger et al., 1985). Over-expression of transfected N-myc genes in neuroblastoma cell lines strongly increases proliferation rates (Bernards et al., 1986; Lutz et al., 1996). Transgenic mice overexpressing N-myc in neural crest-derived tissues show a frequent development of neuroblastoma (Weis et al., 1997). Numerous comparable observations have implicated c-myc and L-myc in the pathogenesis of many other tumor types (Cole, 1986; Marcu et al., 1992; Henrikson and Luscher, 1996).  
           [0009]    The myc-family members are transcription factors with a basic/helix-loop-helix/leucine zipper (bHLHzip) domain. Heterodimers of myc and MAX proteins bind to the E-box motif CACGTG and activate target gene transcription (Blackwood et al., 1992; Alex et al., 1992; Ma et al., 1993). The limited number of identified target genes has precluded the identification of myc downstream pathways. However, many experiments have suggested a role for myc genes in cell cycle control, metastasis, blocking of differentiation, apoptosis and proliferation rate (Henriksson and Luscher, 1996; Dang, 1999; Schmidt, 1999). Phenotypic analysis of mammalian cell lines and drosophila mutants with impaired myc function suggests a role for myc genes in cellular growth. Inactivation of both c-myc alleles in rat fibroblasts resulted in a 2- to 3-fold reduced growth rate (Mateyak et al., 1997). Impaired in vivo expression of drosophila d-myc retards cellular growth and results in adult flies half the normal size. A role for myc genes in growth regulation is further in line with the myc gene&#39;s affect on the cell cycle. Inactivation of c-myc in rat fibroblasts prolonged the G1 and G2 phases of the cell cycle, but not the S phase. High expression of c-myc or N-myc in human cells accelerated transition through the G1-phase (Steiner et al, 1995; Lutz et al., 1996). The same effect was found in drosophila cells, where reduced d-myc activity increased the length of the G1 phase, while increased d-myc expression enhanced transition through G1 (Johnston et al., 1999).  
           [0010]    Many studies have implicated the expression of myc-family oncogenes in metastasis. In several tumor series, a correlation between the expression of myc genes and the occurrence of metastases exists. This was observed for c-myc in breast cancer, bone tumor and colon cancer (Sierra et al., 1999, Gamberi et al., 1998, Kakisako et al., 1998). Experimental systems confirm a direct relationship between expression of myc genes and metastatic capacity. For instance, human-melanoma cells overexpressing c-myc were more metastatic than control melanoma cells (Schlagbauer-Wadl et al., 1999). However, the mechanism of how expression of myc genes increases the metastatic potential of tumor cells is unknown.  
           [0011]    Several direct targets of c-myc, as well as a series of indirectly induced genes, have been identified, but no links between the genes have been found. The incidental and isolated characteristics of the observations preclude the identification of a comprehensive and integrated view of the cellular effects of myc genes in cancer. Examples are prothymosin a (Eilers et al., 1991), ornithine and decarboxylase (Bello-Femandez et al., 1993), the embryonically expressed ECA39 gene (Benvenisty et al., 1992), translation initiation factors elF-4E and eIF-2-alpha (Jones et al., 1996; Rosenwald et al, 1993), the CAD gene (Boyd et al., 1997), the DEAD-box gene MrDb (Grandori et al., 1996) and nucleolin (Greasley et al., 2000). Effects on cyclins and other cell cycle regulators depend on cell types and conditions. Induction of cyclin D1 or tyrosine protein phosphatase cdc25A were found in some model systems (Galaktionov et al.; 1996, Amati et al.; 1998; Philipp et al.; 1994; Daksis et al.; 1994; Solomon et al., 1995). Also, induction of cyclin E and A expression has been reported (Jansen-Durr et al.; 1993; Hanson et al., 1994). The c-myc targets prothymosin a and ornithine decarboxylase are also induced by N-myc, but it is unknown whether c-myc and N-myc share all their targets (Lutz et al., 1996). Thus, it is clear that myc genetic alterations are central and many alterations have been identified and mapped.  
           [0012]    However, much less effort has been spent on elucidating the supporting physiological events that take place in the ever multiplying and spreading cancer cell. The fact that cells undergo genetic changes in their development into cancer cells is well understood. However, how these genetically changed cells recruit and adapt normal physiological mechanisms and events to support the essentially neoplastic character resulting in growth, invasion and spread is much less well understood. For example, the myc proteins are transcription factors which form dimers with the MAX protein and recognize the DNA sequence CACGTG. Further, very few target genes of the myc transcription factors have been identified. The identified myc targets do not permit a clear understanding of the pathway activated by myc proteins and, therefore, the biochemical role of these proteins in pathogenesis is a matter of speculation. Phenotypic observations of mammalian cell lines, transgenic mice and mutant drosophilas with aberrant expression of myc genes have suggested a role for myc genes in cell cycle control, metastasis, apoptosis, proliferation rate and cellular growth.  
         SUMMARY OF THE INVENTION  
         [0013]    The invention discloses that the myc oncogene family provides for the recruitment and adaptation of the normal physiological mechanisms and events to support the essentially neoplastic character of a cancerous cell resulting in growth, invasion and spread. The invention discloses a nucleic acid library comprising myc-dependent downstream genes or functional fragments thereof, wherein the myc-dependent downstream genes are essentially capable of supporting a neoplastic character of cancer such as growth, invasion or spread.  
           [0014]    The phrase a “nucleic acid library” is defined herein as a collection of nucleic acid sequences comprising genes or functional fragments thereof which are downstream myc-dependent genes or functional fragments thereof. Up- or down-regulation of these genes is dependent on the presence of transcription factors encoded by the myc-family members. The nucleic acid sequences may be available in a vector which provides easy handling of the collection of nucleic acid sequences. The downstream myc-dependent genes or functional fragments may be identified by applying the SAGE (Serial Analysis of Gene Expression) technique. Initially, about 66,233 tags were identified, wherein each tag represents an mRNA transcript in a pair of N-myc-transfected and control-transfected neuroblastoma cell lines. Thus, 197 tags have been identified wherein each tag represents a transcript that is specifically induced and 85 tags that are suppressed by N-myc (Table 1). In an extension of these analyses to 79,100 transcripts, an additional series of transcripts were identified that are up- or down-regulated by N-myc (Table 2).  
           [0015]    As used herein, the phrase “functional fragment” will be used to refer to a part of a myc-dependent downstream gene which contains the appropriate Tag-sequence to provide identification by the SAGE technique.  
           [0016]    The invention discloses a nucleic acid library wherein the myc-dependent downstream genes comprise a nucleic acid essentially equivalent to a Tag sequence as shown in Table 1 or Table 2. The phrase “essentially equivalent” as used herein relates to Tag sequences that identify similar or related genes or fragments thereof. In one embodiment, a nucleic acid library is disclosed wherein the myc-dependent downstream genes encode a ribosomal protein, a protein related to protein synthesis, a protein related to metastasis, a glycolysis enzyme or a mitochondrial functional protein.  
           [0017]    The invention also discloses a method for the treatment of cancer comprising modulating a myc-dependent downstream gene capable of supporting an essentially neoplastic character of the cancer, such as growth, invasion or spread. In one embodiment, the invention discloses a method wherein the myc-dependent downstream gene comprises a nucleic acid essentially equivalent to one of the Tag sequences shown in Table 1 or Table 2.  
           [0018]    In one embodiment, the invention discloses downstream genes that are activated or repressed by N-myc in human neuroblastoma. The analysis of the expression level of more than 66,233 transcripts identified 199 up-regulated and 85 down-regulated transcripts in N-myc-expressing cells (Table 1) (Boon et al. 2001). An extension of these analyses to 79,100 transcripts identified an additional series of transcript tags that are up- or down-regulated by N-myc (Table 2). The results show that N-myc functions as a regulator of cell growth, facilitating neoplasia, by stimulating genes functioning in ribosome biogenesis and protein synthesis, as well as in mitochondrial electron transfer and ATP synthesis. Furthermore, many genes involved in cell architecture and cell-matrix interactions are down-regulated, facilitating invasion or spread of the neoplastic cell. A series of the N-myc-regulated genes are targets of c-myc regulation as well.  
           [0019]    The invention herewith discloses a list of MYC-family target genes with a large number of identified targets which permits the identification of pathways induced or inhibited by myc-family genes. However, with the identification of the individual genes, several other practical applications are disclosed. The findings may be used for the development of new drugs, refined use of known drugs and recombinant technology.  
           [0020]    In one embodiment, the invention discloses assays for high-throughput screening of drugs specifically inhibiting myc-proteins or myc-downstream pathway proteins. It is known that an individual cancer is caused by mutations in several oncogenes and/or tumor suppressor genes. Tumors of one and the same tissue can arise from different combinations of mutated oncogenes and tumor suppressor genes. The type and combination of gene defects determine the biology of the tumor cells, and thus the clinical behavior of the tumor. Future tumor therapies may be tailor made for the tumor of individual patients. Upon diagnosis, the type of oncogene activations in a tumor may be established and may guide the choice of therapy.  
           [0021]    There are about 70,000 cancer deaths per year in the U.S. that are associated with defects in myc genes or over-expression of myc genes,(Dang and Lee 1995; Dang, 1999). There are currently no drugs specifically blocking the action of myc proteins. Such drugs may now be identified in high-throughput systems using target genes of the invention, where thousands of compounds may be tested for a specific inhibitory affect on myc proteins. These test-systems may require a very strict read-out system. An example of such a system has been used to identify inhibitors of the TP53 tumor suppressor protein and has been published (Komarov et al., 1999). A lacZ reporter construct was brought under the control of a promoter of a gene known to be induced by TP53. A mouse cell line harboring this construct was used to test 10,000 synthetic chemical compounds. The chemical compounds were added to tissue culture wells with the cells and the compounds that inactivated TP53 were identified by a reduced expression of the LacZ reporter gene.  
           [0022]    The identification of the series of myc-target genes disclosed herein enables a sophisticated approach to identify myc-inhibitory drugs. Currently, there is no sensitive read-out system to identify these drugs. Some target genes of c-myc and/or N-myc have been identified, but their expression levels are only a few times modulated, making them essentially useless as a read-out system (Cole et al., 1999). As disclosed herein, the identification of a series of genes that are strongly induced or suppressed by N-myc and/or c-myc is described.  
           [0023]    In one embodiment, expression of the osteonectin, or SPARC gene, is down-modulated by N-myc from 280 transcripts per 10,000 transcripts in SHEP-2 to 14 transcripts in SHEP-21N is disclosed. This 20-fold reduction is confirmed by Northern blot hybridization of mRNA from SHEP-2 and SHEP-21N (data not shown). Moreover, it is disclosed herein that at the protein level, SHEP-2 cells have more Osteonectin protein than SHEP-2 (data not shown). The Osteonectin protein is known as a secreted protein (Lane and Sage, 1994) which makes testing of N-myc inhibitory drugs using the Osteonectin protein feasible. Test-compounds can be added to SHEP cells wherein N-myc expression can be induced, e.g., by a tetracycline-inducible system. When N-myc expression is induced, Osteonectin protein levels will drop in these cells. If a compound is inhibitory for N-myc, the down-modulation of Osteonectin mRNA expression will be blocked and the cells will continue to secrete Osteonectin protein in the tissue culture medium. Thus, in a multi-well cell culture system, the wells with inactive compounds will have low Osteonectin production. Further, the wells with a high Osteonectin concentration will identify the compounds that inhibit N-myc function.  
           [0024]    Elisa or other protein-based detection systems may be used to automatically detect the wells with high Osteonectin concentrations. Since other down-regulated genes like IGFBP7, collagen type 4a1 and syndecan 2 are identified to be down-regulated by myc, in addition to Osteonectin, these other down-regulated genes may also be used in assays. Similar assays can be designed the other way around using genes induced by N-myc or c-myc as a read-out. Variants of drug-testing systems may use the promoter elements of strongly N-myc-regulated genes and control expression of detectable proteins such as Green Fluorescent Protein. This further simplifies detection of myc-inhibitory drugs in high throughput systems.  
           [0025]    Since it has been shown that many of the N-myc targets are also targets of c-myc, the findings may be used in assays to identify drugs against other members of the myc oncogene family. Inducible c-myc constructs will target the same genes as N-myc in many cell systems. Therefore, the list of target genes disclosed herein for N-myc and c-myc enables the semi-automatic testing of hundreds of thousands candidate drugs and the selection of compounds that are active against myc proteins and/or their downstream pathways.  
           [0026]    The invention also discloses the application and further development of existing drugs for the specific treatment of patients with N-myc or c-myc-activated tumors, such as a method of treatment for myc-related cancer. Future cancer therapies may be designed to specifically inhibit oncogenes that are actually activated in the tumor of a specific patient. As disclosed herein, several known cytostatic or cytotoxic drugs may be used in patients with a tumor caused by activation of a myc gene.  
           [0027]    The invention further discloses a method of treatment comprising using drugs that interfere with nucleophosmin. Nucleophosmin (B23) was identified as a major target of N-myc and c-myc induction. Analysis of a large series of human tumors and cell lines reveals that nucleophosmin mRNA levels also correlate in vivo with N-myc or c-myc expression. Nucleophosmin functions in ribosome biogenesis and nucleolar cytoplasmic transport of pre-ribosomal particles and the protein is known to be translocated from the nucleolus to the nucleoplasm by several cytotoxic drugs, such as actinomycin D, doxorubicin, mitomycin, toyocamycin, tubercidin, sangivamycin and mycophenolic acid (Yung et al., 1995, 1990; Chan et al., 1987; Chan 1988, 1992; Cohen and Glazer, 1985; Perlaky et al., 1997). Thus, treatment of cells with these drugs inhibits processing of ribosomal RNA, protein synthesis and leads to cell death. Several of these drugs are clinically tested and/or applied for treatment of cancer patients.  
           [0028]    Since members of the myc oncogene family induce nucleophosmin mRNA and protein expression, nucleophosmin is an attractive target in the treatment of tumors with overexpression of a myc family member. Thus, fundamental new opportunities for the use of the above mentioned drugs and their analogs exist. The drugs were clinically tested or used on unselected patient series without knowledge of the drug&#39;s possible effect on myc-activated tumors. Presumably, the patient series included patients with and without the involvement of myc genes in the tumors. Actinomycin D was used in Wilms&#39; tumor and rhabdomyosarcoma treatment. It was found that some patients reacted better to therapy than others. A high number of Wilms&#39; tumor and rhabdomyosarcoma patients have high N-myc or c-myc expression (Nisen et al., 1986). Thus, it may be tested whether actinomycin D is specifically effective against N-myc or c-myc-expressing tumors, wherein actinomycin D is ineffective against tumors that have no myc activations.  
           [0029]    Based on these findings, a more specific use of actinomycin D is disclosed. Several other drugs are also effective against nucleophosmin (as described herein). Improvement of these drugs by the development of less toxic analogs with more specific anti-nucleophosmin effects is a strategy disclosed herein to design specific anti-myc drugs. For instance, since toyocamycin is highly toxic (Wilson, 1968), analogs thereof can be tested and further developed for specific use in patients with myc-activated tumors.  
           [0030]    The invention also discloses inhibitors of extracellular and transmembrane proteins. The list of genes induced by N-myc and/or c-myc includes many genes coding for secreted or cell surface proteins. These proteins are excellent targets for drugs because they are readily accessible and may offer targets to specifically inhibit growth or metastasis of tumor cells with an activation of myc-family members. Examples of potential targets are basigin and Plasminogen Activator Inhibitor type 1 (PAI) (Table 1, No. 112). Basigin (also referred to as EMMPRIN, extracellular matrix metalloproteinase inducer) (Table 1, No. 97) is a member of the immunoglobulin family that is present on the surface of tumor cells and stimulates nearby fibroblasts to synthesize matrix metalloproteinases (Guo et al., 1998). Since metalloproteinases are known to promote the degradation of matrix and promote metastasis, drugs that inhibit basigin would be able to prevent metastasis of tumors with high expression of myc-family genes. Drugs inhibiting metalloproteinase are known and may be applied to specifically treat tumors by activating myc-family members.  
           [0031]    Plasminogen activator inhibitor type-i (PAI-1) is a major physiological inhibitor of fibrinolysis and matrix turnover. The down-modulation of PAI-1 by N-myc described herein may increase matrix turnover and promote cell motility and metastasis. Many compounds have been clinically and experimentally tested for regulation of PAI, such as 15-deoxy-Deltal 2, 14-prostaglandin J2 (15d-PGJ2) (an activating ligand for the transcription factor PPARg) has been shown to augment PAI-1 mRNA and protein expression (Marx et al., 1999). As disclosed herein, these drugs may be specifically used to prevent metastasis of N-myc or c-myc-expressing tumors. Furthermore, transmembrane proteins induced by N-myc and/or c-myc proteins may be used as a target of therapeutic drugs, such as antibodies conjugated with cytotoxic drugs.  
           [0032]    The invention further discloses molecular diagnosis of tumors. A first integral description of target genes of myc-family oncogenes is disclosed wherein several functional categories are disclosed. However, in the analysis of fresh tumors for N-myc activation, it was observed that not all these genes or categories of genes are up-regulated in all tumors. This finding suggests that additional defects or factors may affect the range of genes that are induced or repressed by myc oncogenes in individual tumors which is likely to be of importance for the biology of the tumor.  
           [0033]    The detailed analysis of up-regulated/suppressed genes in tumors for activation of a myc-family member is clinically relevant. A tumor with up-regulation of genes involved in protein synthesis may differ from a tumor with up-regulation of genes involved in oxidative phosphorylation. This is important for selecting the appropriate treatment modality for a tumor. The full list of N-myc and/or c-myc downstream targets thus discloses an important means to classify tumors for optimal therapeutic regimens. This finding may be applied in the development of diagnostic kits that measure the activation or inactivation of key-downstream targets of myc-family oncogenes. Such diagnostic tools are may be provided to guide the optimal therapy.  
           [0034]    Further, the invention discloses non-invasive diagnosis of tumors. Activation of specific oncogenes is currently established by the analysis of a surgically removed tumor specimen. As surgery is a burden on the patient, expensive and not without risk, non-invasive methods to monitor the oncogene status of tumors are desirable. The inventory of genes for secreted proteins that are induced or suppressed by N-myc may be used to determine the status of myc expression by the analysis of serum markers. Further, serum levels of these genes may be used to monitor tumor growth, reaction to therapy and occurrence of relapses. The results described herein show that many candidate proteins, e.g., osteonectin (reduced from 280 to 14 tags/i 0,000 tags), macrophage migration inhibitory factor (Table 1, No. 92) (induced from 1.1 to 14.4 tags/10,000 tags) and Plasminogen activator inhibitor type 1 (PAI-1), may be used as serum markers to aid in the biological classification of tumors. Recently, serum levels of PAI-1 were analyzed in a series of head and neck tumors and found to correlate with tumor stage (Strojan et al., 1998). Therefore, PAI-1 and other secreted proteins were identified to be good candidates to monitor the status of myc genes in a tumor and to follow the growth and response of therapy on myc-induced tumors.  
           [0035]    The invention further discloses enhancement of cellular protein synthesis machinery for production purposes. Eukaryotic cells may be used to produce recombinant proteins, such as drugs. The discovery that N-myc and c-myc induce essential components of the protein synthesis machinery may be applied to boost production of recombinant proteins in cell systems. The invention discloses the use of cells with a high expression of endogenous or transfected myc genes to optimize the yields of recombinant proteins, such as antibodies, hormones or other proteins with therapeutic or commercial value.  
           [0036]    The invention further discloses a method to identify a substance capable of interfering with n-myc or n-myc-induced modulation of transcripts and/or proteins, comprising providing a cell with n-myc activity or a nucleic acid encoding n-myc activity and determining the modulation of the transcripts and/or proteins in the presence of the substances. As disclosed herein, the modulation of transcripts and/or proteins by n-myc can be either up- or down-regulated. 
       
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0037]    [0037]FIG. 1. Northern blot analysis of N-myc downstream target genes. Equal amounts of total RNA from exponentially growing SHEP-2 and SHEP-21N cells were loaded. Northern blots were hybridized with probes for the 23 indicated N-myc targets.  
         [0038]    [0038]FIG. 2. Level of induction of the 56 ribosomal protein genes identified as N-myc targets (p&lt;0.01) in SHEP-21N cells. FIG. 2A: Fold induction by N-myc in SHEP-21N as a function of the basic expression levels in SHEP-2. X-coordinate: basic expression level in SHEP-2 normalized per 10,000 tags. Y-coordinate: fold induction in SHEP-21N. FIG. 2B: Increase of the same 56 ribosomal protein genes in N-myc-amplified neuroblastoma N159 as a function of the basic expression level in N-myc single copy neuroblastoma N52. X-coordinate: expression level in N52 normalized per 10,000 tags. Y-coordinate: Fold increase in N159 relative to N52.  
         [0039]    [0039]FIG. 3. Time-course analysis of N-myc and downstream target gene induction in SHEP-21N cells. SHEP-21N cells were treated for 24 hours with 10 ng/ml tetracycline, washed and grown for an additional 36 hours without tetracycline. Cells were harvested at 0 hour, 8 hours and 24 hours of tetracycline treatment. Subsequent samples were taken at 1 hour, 2 hours, 4 hours, 8 hours, 10 hours, 12 hours, 24 hours and 36 hours after removal of the antibiotic. FIG. 3A: Northern blot analysis of total RNA at indicated time points. FIG. 3B: Western blot analysis of N-myc protein at indicated time points. 10 mg of total protein samples of the time-course experiment were fractionated through a 10% SDS-PAGE gel, blotted on Immobilon membrane and probed with a monoclonal anti-N-myc antibody.  
         [0040]    [0040]FIG. 4. Nucleolin and Nucleophosmin protein expression and total RNA content of SHEP-2 and SHEP-21N. FIG. 4A: Western blot analysis of nucleolin, N-myc and nucleophosmin protein expression. Total cell extracts (10 μg) were fractionated through an acrylamide gel, blotted and probed with polyclonal antibodies against nucleolin (upper panel), monoclonal antibodies against N-myc (middle panel) and nucleophosmin (lower panel). Control cell lines IMR32 and SK-N-FI have high and low expression, respectively, of N-myc, nucleolin and nucleophosmin. FIG. 4B: Total RNA content of SHEP-2 and SHEP-21N. RNA was isolated from ten samples of 10 6  cells of each cell line and photospectromerically analyzed. Error bars give the S.D.  
         [0041]    [0041]FIG. 5. Northern blot analysis of total RNA from neuroblastoma cell lines and tumors. Filters were hybridized with indicated probes. RNA quantification was checked by ethidium bromide staining and the 28S band is shown. FIG. 5A: panel of 21 neuroblastoma cell lines. FIG. 5B: Panel of 16 fresh tumors. Tumors in lanes 1-9 are N-myc-amplified.  
         [0042]    [0042]FIG. 6. Northern blot analysis of induction of N-myc target genes in a c-myc-transfected melanoma cell line. Clone 3 is a c-myc-transfected clone of the IGR39D melanoma cell line. Equal amounts of total RNA of IGR39D and clone 3 were loaded. Filters were hybridized with the indicated probes. 
     
    
     DETAILED DESCRIPTION  
       [0043]    The members of the myc oncogene family play an important role in cancer. The frequency of genetic alterations of myc genes in human cancers (Dang and Lee, 1995) has allowed an estimation that approximately 70,000 cancer deaths occur per year in the United States and are associated with changes in myc genes or in myc gene expression. Three members, N-myc, c-myc and L-myc are rearranged, amplified, mutated and/or over-expressed in many cancers of the lung, breast, colon, in various leukemias and brain tumors. The myc proteins are transcription factors that form dimers with the MAX protein and recognize the DNA sequence CACGTG. Very few target genes of the myc transcription factors have been identified thus far, and the identified targets do not permit a clear understanding of the pathway activated by myc proteins. Therefore, the biochemical role of these proteins in pathogenesis is a matter of much speculation. Phenotypic observations of mammalian cell lines, transgenic mice and mutant drosophilas with aberrant expression of myc genes have suggested a role for myc genes in cell cycle control, metastasis, apoptosis, proliferation rate and cellular growth.  
         [0044]    To identify the downstream pathways of the myc genes, the SAGE (Serial Analysis of Gene Expression) technique was utilized. Initially, about 66,233 tags were identified, each representing an mRNA transcript in a pair of N-myc-transfected and control-transfected neuroblastoma cell lines. Thus, 197 tags have been identified, wherein each tag represents a transcript that is specifically induced and 85 tags have been identified that are suppressed by N-myc (Table 1). By extending these analyses to 79,100 transcripts, an additional series of transcripts were identified that are up- or down-regulated by N-myc (Table 2). N-myc appears to induce the expression of many ribosomal protein genes that are involved in ribosomal RNA synthesis, ribosome biogenesis and genes involved in translation and protein maturation. This indicates that a major function of N-myc is the enhancement of the protein synthesis machinery of the cell. Furthermore, a striking induction of genes involved in glycolysis, electron transport and ATP synthesis was observed in the mitochondria. This suggests an increased capacity of the cellular energy production mechanism.  
         [0045]    Another set of N-myc targets is involved in cellular adhesion, matrix formation, invasive capacity and cytoskeletal architecture. This data explains the increased metastatic potential associated with myc-expressing tumor cells. Furthermore, a set of genes is induced or suppressed with a role in transcription, chromosome condensation and signal transduction. Finally, a series of genes are identified for which only a short cDNA sequence is known (Ests) and some SAGE transcript tags were identified without a gene assignment. These unidentified genes may be important components of the N-myc downstream pathway. Many of the downstream targets of N-myc appear to be targets of the c-myc oncogene as well. Therefore, the data presented herein represents an inventory of target genes of the myc oncogene family. As these genes mediate the tumorigenic effects of myc-family oncogenes, the genes offer the opportunity to identify new drugs that inhibit myc proteins or myc downstream pathways. Further, the genes represent a range of potential target genes to inhibit or kill tumor cells that express members of the myc-family of oncogenes.  
         [0046]    Results.  
         [0047]    SAGE libraries of N-myc-transfected neuroblastoma cell lines.  
         [0048]    To identify the downstream target genes of N-myc, the SAGE technique was used on an N-myc-transfected neuroblastoma cell line. The SHEP cell line has no N-myc amplification and expression, and no c-myc expression. A tetracycline-dependent N-myc expression vector was introduced in these cells, resulting in the SHEP-21N clone (Lutz et al., 1996). The SHEP-21N cells have constitutive exogenous N-myc expression that can be switched off by tetracycline. N-myc expression in the SHEP-21N cells was shown to increase the rate of cell division, shorten the GI phase of the cell cycle and to render the cells more susceptible to apoptotic triggers (Lutz et al., 1996; Fulda et al., 1999).  
         [0049]    Two SAGE libraries were constructed; one from SHEP-21N cells expressing N-myc and one from the SHEP-2 control cells. The SHEP-2 clone was transfected with the empty expression vector. About 44,674 transcript tags were sequenced from SHEP-2 and 21,559 transcript tags were sequenced from the SHEP-21N library. Comparison of the two SAGE libraries yielded 199 significantly (p&lt;0.01) up-regulated tags in N-myc-expressing cells, with induction levels of up to 47-fold (Table 1, section 1). Another 85 tags were significantly down regulated. Further sequencing of the SHEP-21N library from 21,559 tags to 34,426 tags yielded another series of transcript tags that were either up- or down-regulated by N-myc (p&lt;0.01) (Table 2). Table 2 describes these tags and the most likely gene assignment that corresponds to the tags. The transcripts corresponding to the tags were identified using a computer program (Caron et al., 2001) and using the SAGEmap database from CGAP/NCBI (Lal et al., 1999). Seven groups of N-myc-regulated genes are disclosed.  
         [0050]    N-myc targets 1: ribosomal protein genes.  
         [0051]    The first functional group includes 61 ribosomal protein genes that were induced up to 47-fold (p&lt;0.01, Table 1, section 1). The 61 proteins represent about 75% of the human ribosomal proteins (Wool et al., 1996). Seven of the induced genes were selected for further analysis. Northern blots with equal amounts of total RNA from SHEP-2 and SHEP-21N cells were hybridized with probes for the ribosomal proteins S 12, S27, Fau-S30, L8, S6, S 19 and the ribosomal phosphoprotein P0 (PPARP0) (FIG. 1). The seven genes were induced by N-myc. The total amount of tags found for ribosomal protein mRNAs comprises about 4% of all tags in SHEP-2. This fraction increased to 10% in SHEP-21N. The level of induction of individual ribosomal protein genes is a function of their basal expression levels in SHEP-2. Highly expressed genes are less induced than genes with a low basic expression in SHEP-2 (FIG. 2A). The results indicate that N-myc induces, directly or indirectly, the mRNA expression level of the majority of ribosomal proteins.  
         [0052]    2N-myc targets 2: genes functioning in ribosome biosynthesis and protein synthesis.  
         [0053]    A second functional group of 26 tags corresponds to genes with a distinct role in protein synthesis and turnover, notably ribosome biogenesis, mRNA translation, protein maturation and degradation.  
         [0054]    The induction of nucleophosmin (B23) (Table 1, nos. 67 and 83) was observed. Northern blot analysis confirmed the induction (FIG. 1) to a level stronger than suggested by the tag frequencies. Nucleophosmin is a highly abundant nucleolar protein that processes ribosomal RNA by cleavage of the 5′ end of the 5.8S pre-rRNA (Savkur et al., 1998). Nucleophosmin also functions in assembly and nuclear-cytoplasmic shuttling of pre-ribosomal particles (Borer et al., 1989; Olson et al., 1991; Szebeni et al, 1999). Nucleophosmin is the target of recurrent chromosomal translocations in lymphomas and leukemia (Morris et al., 1994; Redner et al., 1996; Pandolfi, 1996). The SAGE libraries were also analyzed for other genes implicated in the process of nucleophosmin&#39;s role in ribosome biogenesis. Nucleolin, which also has two tags attributed to alternative transcripts (Table 1, nos. 87 and 88), is induced from 2.5 to 5.6 tags per 10,000 in total (p=0.044). This induction was confirmed by Northern blot analysis (FIG. 1). Nucleolin is also a highly abundant nucleolar protein that binds to nucleophosmin (Tujeta and Tujeta, 1998; Ginisty et al., 1999). Nucleolin is probably a rate-limiting enzyme for the first step in the processing of the pre-ribosomal RNA to mature 18S rRNA (Gistiny et al, 1998). Nucleolin is furthermore involved in the assembly of pre-ribosomal particles and their nucleo-cytoplasmic transport that interacts with 18 ribosomal proteins (Bouvet et al., 1998), sixteen of which are induced by N-myc. The induction of nucleolin and nucleophosinin by N-myc suggests that in addition to ribosomal proteins, ribosomal RNA and ribosome biosynthesis are also targets of N-myc stimulation.  
         [0055]    Tags corresponding to three translation initiation factors and five translation elongation factors were also induced. The initiation factors are eukaryotic translation initiation factor 3 subunit 8 (eIF3s8) (Table 1, No. 81) and subunit 3 (Table 1, No. 78), and eukaryotic translation initiation factor 4B (Table 1, No. 72). Elongation Factor 1 (EEF1), responsible for delivery of aminoacyl-tRNA to the ribosome, is a heterotrimer including the subunits alpha/beta/gamma or alpha/delta/gamma. The tags for the subunits alpha, delta and gamma are induced 9- to 11.4-fold in SHEP-21N (Table 1, Nos. 69, 66 and 70). Elongation Factor 2, which promotes the translocation of the nascent polypeptide chain from the A- to the P-site of the ribosome, is also induced (Table 1, No. 79). The mitochondrial elongation factor Tu (tuFM), which delivers aminoacyl-tRNA to the mitochondrial ribosomes, is 12.4 times up-regulated (Table 1, No. 64). Northern blot analysis of SHEP-21N and SHEP-2 confirmed the induction of eIF3s8, EEF1a1 and tuFM (FIG. 1). This data further supports a role for N-myc as a regulator of protein synthesis.  
         [0056]    Protein synthesis also includes the steps of maturation and routing. The nascent polypeptide-associated complex (NAC) alpha mRNA was induced in N-myc-expressing cells (Table 1, No. 77). NAC protects nascent polypeptide chains of cytosolic proteins from inappropriate translocation to the endoplasmatic reticulum (Wiedmain et al., 1994). Induction of the chaperones HSP60 and HSP90 further suggested an increased cellular capacity for protein folding and maturation (Table 1, Nos. 65, 68, 80 and 82). HSP60 is implicated in mitochondrial protein import and macromolecular assembly. HSP90 is involved in the folding of a signaling molecule including steroid-hormone receptors, kinases and the refolding of misfolded proteins. Northern blot analysis confirmed the induction of HSP60 (FIG. 1). The cellular capacity for protein degradation was possibly induced which was suggested by the increased tag frequencies for three ubiquitin pathway proteins (Table 1, Nos. 62, 73 and 76) and five proteasome subunits (Table 1, Nos. 63, 71, 74, 75 and 84). Northern blot analysis confirmed the higher expression level of proteasome subunit b type 6 in SHEP-21N cells (FIG. 1).  
         [0057]    N-myc targets 3: glycolysis genes.  
         [0058]    A third group of N-myc-induced genes encoded key-enzymes in the glycolytic pathway (Table 1, section 4). Tags for aldolase A fructose-biphosphate (ALDOA), triosephosphate isomerase 1 (TPI1), glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and pyruvate kinase are increased (Table 1, Nos. 133, 135 and 132). Other induced mRNAs encode for the metabolic enzymes 3-phosphoglycerate dehydrogenase involved in the synthesis of serine and sorbitol dehydrogenase that oxidizes sorbitol to fructose. Aldehyde dehydrogenase 1 functions in ethanol metabolism. Northern blot analysis confirmed the mRNA induction of ALDOA, pyruvate kinase, TPI1 and GAPDH (FIG. 1). These data implicate glycolysis proteins as a target of N-myc stimulation.  
         [0059]    N-myc targets 4: Mitochondrial electron carriers and ATP synthethase.  
         [0060]    SHEP-21N shows induction of a series of tags corresponding to genes with a role in oxidative phosphorylation in the mitochondria (Table 1, section 5). Seventeen tags are significantly induced. Five of the induced genes are mitochondrially-encoded. (See, Welle et al., 1999.)  
         [0061]    The oxidation of NADH and FADH2 by electron transfer to O 2  is performed by three protein complexes of the respiratory chain, NADH-dehydrogenase, ubiquinol-cytochrome c reductase and cytochrome c oxidase. These large complexes establish a proton gradient across the mitochondrial inner membrane and drive the synthesis of ATP by the F-type ATP synthase complex. N-myc induces a series of subunits of all four enzyme complexes.  
         [0062]    Four NADH dehydrogenase subunits, subcomplex 4 (Table 1, No. 136; NDUFB4), subcomplex 7 (Table 1, No. 138) and the mitochondrially encoded subunits 4/41 and 3 (Table 1, Nos. 150 and 151) are induced. The induction of NDUFB4 was confirmed by Northern blot analysis (FIG. 1).  
         [0063]    One subunit of the ubiquinol-cytochrome c reductase complex was induced (Table 1, No. 136). Furthermore, subunits II, III and VIII of cytochrome c oxidase were induced in N-myc-expressing cells. Induction of the subunit VIII (COXVIII, Table 1, No. 149) was confirmed by Northern blot analysis.  
         [0064]    N-myc induces the transcripts of subunits 6/8 of the F0 segment and of two isoforms of subunit 9 (or c) of the F0 segment of the stalk of the F-type ATP synthase (Table 1, Nos. 137,148, and 152). ATPase subunits 6 and 8 are encoded on an overlapping mitochondrial transcript.  
         [0065]    Several other proteins with a role in mitochondrial function are also up-regulated (Table 1, section 5). The voltage-dependent anion channel (VDAC, Table 1, No. 143) was induced 5-fold, which was confirmed by Northern blot analysis (FIG. 1). VDAC forms a mitochondrial outer membrane channel that allows diffusion of small hydrophylic molecules and plays a major role in apoptosis as it can transfer cytochrome c to the cytoplasm, resulting in caspase 9 activation.  
         [0066]    Glutathione peroxidase 4 and glutathione S-transferase p are also strongly induced (Table 1, Nos. 139 and 144). Glutathione readily accepts electrons and may serve as a scavenger for hydrogen peroxide and organic peroxides, the inevitable artifacts produced by the electron transport chain of the mitochondria. The reaction is catalyzed by glutathione peroxidase.  
         [0067]    N-myc targets 5: genes with a role in cell motility and metastasis.  
         [0068]    A large group of tags that are either induced or suppressed by N-myc belong to genes with a role in cell motility and cell-matrix interactions (Table 1, section 3). These genes encoded cytoskeletal proteins, cell surface proteins, adhesion molecules and extracellularly secreted proteins with a role in cellular matrix architecture and turnover. Ten tags for genes in this category were significantly induced. Another 29 tags in this category are significantly down-modulated. Examples of down-regulated genes include Collagen types Ia1 (Table 1, Nos. 100, 108 and 109), type IVa1 (Table 1, No. 115) and type XVIIIa1 (Table 1, No. 116), fibrillin (Table 1, No. 121), syndecan 2 (Table 1, No. 126), fibronectin (Table 1, No. 122) and Osteonectin (SPARC) (Table 1, Nos. 118, 123 and 125). Osteonectin is down-modulated from 208 to 14 tags per 10,000 tags. Down-modulation of Osteonectin, syndecan 2, collagen IVa1 and Plasminogen activator inhibitor type 1 (Table 1, No. 112) were confirmed by Northern blot analysis (data not shown). The down-modulation of these genes suggests that N-myc can reduce the adherence of cells to the cellular matrix and, therefore, induce the motility of the cells which is in line with an enhanced metastatic potential of myc-expressing tumor cells.  
         [0069]    N-myc targets 6: other genes.  
         [0070]    Another group of genes affected by N-myc is formed by signal transduction proteins, transcription factors, chromatin factors, cyclins and other regulatory proteins. This group includes 66 significantly induced transcripts (Table 1, section 6). Examples are NM23A, NM23B, HMG I-Y and zinc finger protein 6 (Table 1, Nos. 171,214,162 and 218). Induction of HMG I-Y, NM 23A and NM23B was confirmed by Northern blot analysis (data not shown). Another group of genes of regulatory proteins or enzymes were down-modulated by N-myc (Table 1, section 6). Examples are Insulin-like growth factor binding protein 7 (IGFBP7) (Table 1, No. 52) and zinc-finger protein 216 (Table 1, No. 248). Northern blot analysis confirmed down-regulation of IGFBP7 in SHEP-2 cells as compared to SHEP-21N cells (data not shown).  
         [0071]    N-myc targets 7: Anonymous genes (Ests).  
         [0072]    A series of anonymous genes for which only a partial cDNA sequence is known (expressed sequence tags or Ests) are induced or down-modulated by N-myc (Table 1, section 7). The function of these genes is unknown, but the finding that the genes are targets of myc regulation mark them as potentially important genes with a role in cancer.  
         [0073]    Tags of unidentified targets of N-myc.  
         [0074]    For several tags that were differentially represented in the SHEP-2 and SHEP-21N libraries, the corresponding genes have not yet been identified (Table 1, section 8). These tags belong to genes that are induced or suppressed by N-myc.  
         [0075]    N-myc activates downstream targets within 4 hours.  
         [0076]    In a time-course experiment, whether the putative N-myc targets are induced after N-myc modulation in the SHEP-21N system was analyzed. N-myc expression can be reversibly switched off in SHEP-21N cells by tetracycline. SHEP-21N cells were treated for 24 hours with tetracycline, washed extensively and grown for an additional 2 to 36 hours without tetracycline. Northern blot analysis showed that the expression of N-myc mRNA is switched off within 8 hours of tetracycline treatment (FIG. 3A, lanes 1-2). After removal of tetracycline, N-myc mRNA expression is restored between 2 and 4 hours (FIG. 3A, lanes 5-6).  
         [0077]    The N-myc protein expression was analyzed by Western blotting in a parallel time-course experiment and closely followed the N-myc mRNA expression (FIG. 3B). The Northern blot filters were hybridized with probes for the N-myc downstream targets nucleolin, nucleophosmin and the ribosomal protein genes RPS6 and RPS12 (FIG. 3A). After repression of N-myc by tetracycline, the mRNA levels of these genes remain unaffected at 0 and 8 hours, but their expression was reduced to low basic levels at 24 hours. Importantly, between 2 and 4 hours after re-expression of N-myc mRNA and protein, expression of all four genes was strongly re-induced (FIG. 3B, lanes 6-7).  
         [0078]    Similar results were obtained for EEF1A1, TPI1, eIF3 s8, and VDAC (data not shown). The expression level of cofilin that was used as a control does not significantly change during the time course. To exclude a direct effect of tetracycline on nucleolin or nucleophosmin expression, the same experiment was performed with SHEP-2 cells, but no effect on gene expression was observed (data not shown). These results confirm that genes identified herein indeed are induced by N-myc. The results also show that the identified genes are early targets in the N-myc downstream pathway, although not necessarily direct targets of N-myc. Therefore, the identified genes represent essential components of the N-myc pathway. The data further show that the induction by N-myc is highly versatile, as expression drops after N-myc abrogation and is swiftly restored after N-myc re-expression.  
         [0079]    N-myc induces ribosomal RNA synthesis.  
         [0080]    Since the induction of two genes with a key role in rRNA processing and ribosome biogenesis exist, an analysis of their protein expression level and their possible functional activity was performed. Protein expression of nucleolin and nucleophosmin was analyzed in SHEP-2 and SHEP-21N cells, as well as in two control cell lines with and without N-myc amplification. Western blot analyses showed a higher nucleolin and nucleophosmin expression in SHEP-21N compared to SHEP-2 (FIG. 4, lanes 3 and 4) and in the N-myc-amplified IMR32 cell line compared to the N-myc single copy cell line SK-N-FI (FIG. 4, lanes 1 and 2). As these proteins function in ribosomal RNA processing, whether SHEP-21N has a higher rRNA content than SHEP-2 cells was analyzed. Total RNA was isolated from 10 samples of 10 6  exponentially growing cells of each of the cell lines. Spectrophotometric analysis revealed that SHEP-21N cells have, on average, 45% higher yield of total RNA than SHEP-2 cells (p&lt;0.001, Student T test for independent samples) (FIG. 4B). Duplicate experiments on independently cultured cells gave the same results. Densitometric quantification of the 18S and 24S rRNA bands fractionated by agarose gel electrophoresis confirmed that this increase is caused by ribosomal RNA (data not shown).  
         [0081]    To analyze whether this strong increase in rRNA resulted in increased ribosomal function and overall protein synthesis, protein content and the rate of protein synthesis was measured in SHEP-2 and SHEP-21N cells. Lysates of 10 6  SHEP-2 and SHEP-21N cells contained equivalent amounts of protein (data not shown). Protein synthesis rates were analyzed by  35 S-methionine incorporation. No differences were observed between SHEP-2 and N-myc-expressing SHEP-21N cells. Manipulation of the N-myc expression in SHEP-21N in a time course experiment also did not reveal any difference in protein synthesis rates (data not shown). This suggests that the protein synthesis rate in SHEP-21N is either limited by a factor not induced by N-myc, or that protein synthesis is already maximal in the SHEP neuroblastoma cell line and beyond a level that can be boosted by N-myc.  
         [0082]    SAGE libraries of neuroblastomas with and without amplification of endogenous N-myc.  
         [0083]    Since the SHEP neuroblastoma cell line has no endogenous N-myc expression, the N-myc-transfected cells do not necessarily have a genetic background representative for N-myc-amplified neuroblastomas. For example, 90% of the N-myc-amplified neuroblastomas have deletions of the chromosomal region 1p35-36 (Caron et al., 1993), while the SHEP-2 and SHEP-21N cells have two apparently intact p arms of chromosome 1 (data not shown). To address the question whether the downstream pathway of N-myc identified herein is also in vivo activated, SAGE libraries of two neuroblastomas were generated. Neuroblastoma tumor N159 has N-myc amplification and expression and neuroblastoma N52 is an N-myc single copy tumor without N-myc expression (FIG. 5B, lanes 9 and 10). 39,598 tags of the two libraries were sequenced. The tag frequencies were normalized per 20,000 tags and compared. N-myc was represented by 16 tags in N159 and 0 tags in N52. There are 52 tags differentially expressed (p&lt;0.01) in the libraries. These differences are probably partly caused by N-myc, as the two tumors are likely to differ in more aspects. The N-myc target genes identified in the SHEP cells that correlate with N-myc in the two tumors were analyzed.  
         [0084]    The 56 significantly (p&lt;0.01) induced ribosomal protein genes detected in SHEP-21N produce a total of 988 tags in N52 and 1600 tags in N159 (per 20,000 tags). The N-myc-amplified N159 tumor therefore has a 62% higher ribosomal protein gene expression. There are 36 tags with an increase of at least 50% and 22 tags with an increase of at least 100% in N159 when compared to N52 (FIG. 2B). These increases are more moderate than the SHEP-21N cells (compare FIGS. 2A and 2B), but strongly suggest that N-myc induces ribosomal protein gene expression in vivo.  
         [0085]    Other genes functioning in protein synthesis are also up-regulated in N159. Increased expression in N159 compared to N52 is seen for nucleophosmin (from 4 to 19.2 tags), nucleolin (3 to 9 tags), eukaryotic translation initiation factor 4A, isoform 1 (4 to 9 tags), the translation elongation factors EEF1a1 (50 to 96 tags) and EEF1g (18.4 to 32.8 tags). There is almost no induction of the genes involved in glycolysis and oxidative phosphorylation. The expression levels of five representative genes were confirmed by hybridization of Northern blots with total RNA from N159 and N52 (FIG. 5B and data not shown). These results show that the expression levels of many of the N-myc target genes identified in the SHEP-21 N cells are also in vivo correlated with N-myc amplification and overexpression. However, this does not hold for all genes, suggesting that other factors modulate the activity of N-myc target genes.  
         [0086]    N-myc target gene expression analyzed in panels of neuroblastoma cell lines and tumors.  
         [0087]    To further analyze the induction of N-myc downstream genes in neuroblastoma, the expression of the genes was examined in a panel of neuroblastoma cell lines and tumors. Hybridization of a Northern blot of total RNA from 21 neuroblastoma cell lines showed a fair, albeit imperfect, correlation between expression of N-myc, nucleolin, nucleophosmin and the ribosomal protein PPARP0 (FIG. 5A). Cell line SJNB12 has no N-myc expression, but a very high expression of the N-myc target genes. However, this cell line has c-myc amplification and over-expression (FIG. 5A, lane 7 and Cheng et al., 1995), suggesting that c-myc may induce the same target genes as N-myc (as described herein).  
         [0088]    As cell lines are not fully representative of neuroblastoma tumors in vivo, 16 fresh neuroblastomas were analyzed including the aggressive stages 3 and 4 and the less aggressive stages 1, 2 and 4s. A Northern blot analysis showed a fair, overall correlation between expression of N-myc, nucleolin and nucleophosmin (FIG. 5B). There are some exceptions, but the overall results suggest that nucleolin and nucleophosmin are also in vivo targets of N-myc induction. Ribosomal protein S6 (RPS6) expression showed a less consistent relationship with N-myc, indicating that in addition to N-myc, other factors may also modulate its expression.  
         [0089]    Several N-myc target genes are induced or suppressed by c-myc in addition to N-myc, and belongs to the same family of proto-oncogenes as c-myc. Since both oncogenes induce similar phenotypic effects and share several target genes, whether the N-myc downstream targets identified in this study are targets of c-myc as well were analyzed. Therefore, the melanoma cell line IGR39D) and a c-myc-transfected clone of this cell line (clone 3, Versteeg et al, 1988) were analyzed. Northern blots with total RNA of these cell lines were hybridized with the 26 probes tested on the SHEP-2 and SHEP-21N cells. 9 of 23 N-myc-induced targets appeared to be induced by c-myc as well (FIG. 6) and include the ribosomal protein genes S12, S27, S 19, S6, nucleolin, nucleophosmin, ubiquitin, GAPDH and NDUFB4. Three of the N-myc-suppressed targets were tested and found to be suppressed by c-myc as well and include Osteonectin (Table 1, Nos. 118, 123 and 125), Plasminogen activator inhibitor type 1 (Table 1, No. 112) and connective tissue growth factor (Table 1, No. 127). Therefore, c-myc and N-myc share about 46% of their target genes in the cell systems tested herein including nucleophosmin, nucleolin and most ribosomal protein genes.  
         [0090]    86 transcripts were found to contribute to ribosome biogenesis, mRNA translation, protein maturation and protein turnover, demonstrating that enhancement of protein synthesis is a major function of N-myc. A striking 45% higher rRNA content was found in SHEP-21N than in SHEP-2. No overall increase was observed in the rate of protein synthesis in SHEP-21N. One interpretation is that some rate limiting components of the protein synthesis machinery are not induced in SHEP-21N cells. The SAGE libraries of the N-myc single copy neuroblastoma N52 and the N-myc-amplified tumor N159 showed that the ribosomal protein genes, nucleolin, nucleophosmin and five translation initiation and elongation factors are over-expressed in the N-myc-amplified neuroblastoma in vivo. The Northern blot analysis of 37 neuroblastomas and neuroblastoma cell lines further confirmed induction of these genes in N-myc-amplified neuroblastoma. These results show that myc genes function as major regulators of protein synthesis which is in line with the reduced rate of protein synthesis in fibroblasts with a homozygous inactivation of c-myc (Mateyak et al., 1997) and the increased protein synthesis in fibroblast after activation of c-myc (Schmidt, 1999).  
         [0091]    Energy production, mitochondria and apoptosis.  
         [0092]    Other comprehensive sets of N-myc downstream target genes are implicated in the glycolysis, the mitochondrial electron transfer and ATP synthesis pathways. The identification of the electron transfer and ATP synthesis pathway as a major target of N-myc induction bears on the relationship between the mitochondrial transmembrane potential and apoptosis. Mitochondria have two faces as they provide the energy for fast cycling cells and can drive the cell into apoptosis. Similarly, the myc oncogenes can induce vigorous cell proliferation as well as massive apoptosis. N-myc expression renders SHEP-21N cells susceptible to apoptotic triggers (Fulda et al., 1999; Lutz et al., 1998). Many key events in apoptosis focus on mitochondrial membrane potential (Green and Reed, 1998). Examples are cytochrome c release, hyperpolarization of the inner membrane, opening of the permeability transition pore and generation of reactive oxygen species (ROS). During normal electron transport in the mitochondrial membrane, 1 to 5% of the electrons lose their way and generate ROS. Any interruption of the electron transfer pathway strongly increases ROS production with a deleterious effect on the cell (Kroemer et al., 1997).  
         [0093]    Enhancement of the electron flow by N-myc would, upon interruption of the electron transfer chain, boost ROS production. In addition, the moderate up-regulation of VDAC (FIG. 1) could stimulate cytochrome c release and apoptosis. Therefore, N-myc induction of the electron transfer genes provides the energy required for cell proliferation. Meanwhile, it could increase the deadly potential of the mitochondria and upon triggering, tip the scale towards execution of apoptosis.  
         [0094]    Tags for oxidative phosphorylation pathways are not over-expressed in the N-myc-amplified N159 tumor. This tumor might have been selected in vivo for additional defects that interfere with part of the N-myc downstream pathway. While SHEP-21N cells expressing N-myc are susceptible to apoptotic triggers (Lutz et al., 1998), neuroblastoma cell lines with overexpression of endogenous N-myc are refractory to such triggers. This shows that these cell lines have defects in the pro-apoptotic arm of the N-myc downstream pathway.  
         [0095]    N-myc and c-myc share target genes.  
         [0096]    To date, only two target genes of N-myc have been published and are targets of c-myc as well (Lutz et al., 1996; Eilers et al., 1991; Bello-Fernadez et al., 1993). Of the 23 up-regulated targets of N-myc that were tested on Northern blots, 9 are induced by c-myc in transfected melanoma cells. Both down-regulated N-myc targets that were tested were also down-regulated by c-myc. Since the N-myc-induced downstream pathway genes form very concise functional groups of genes, it was postulated that N-myc may function as a general stimulator of protein synthesis and energy production. Since c-myc has an equally powerful growth-inducing and transforming effect as N-myc, it is difficult to envisage that c-myc would only induce a subset of the genes that are necessary to boost the protein and ATP synthesis machineries. It appears that N-myc and c-myc activate the same basic cellular functions. Indeed, c-myc is implicated in induction of protein synthesis in fibroblast cell lines (as described herein). Induction of genes by N-myc strongly depends on their basic expression levels (FIG. 2). It is therefore possible that high expression of potential target genes in the original melanoma cell line may have prevented their induction by c-myc.  
         [0097]    The physiological role of myc genes has been enigmatic, as only very few target genes have been identified thus far. 351 transcript tags are described that identify 335 genes defined by their unigene number that are targets of N-myc or potential targets of N-myc, some of which are targets of c-myc as well. Myc genes thus function as major regulators of protein synthesis and cellular energy production and it is likely that this induction mediates the enhanced transition through the G1 phase of the cell cycle in normally proliferating cells and in cells that are induced to proliferate by physiological stimuli. The effect on protein synthesis confirms earlier postulations based on the identification of a limited set of target genes (Schmidt, 1999; Mateyak et al., 1997; Johnston et al., 1999). The stimulatory effect on genes in the electron transfer and ATP synthesis pathway is unexpected and fits well with the energy requirements for enhanced protein production, GI transition and could also relate to the apoptotic effect of myc genes.  
         [0098]    List of tags and genes induced or suppressed by N-myc.  
         [0099]    Table 1 lists the tags that were found to be significantly (p&lt;0.01) induced or suppressed by N-myc in the comparison of the SHEP-2 and SHEP-21N SAGE libraries. Table 1A is disclosed to designate the nucleotide sequences of at least some of the tags of Table 1. The comparison is based on 21,559 tags of SHEP-21N and 44,674 tags of SHEP-2. The tag frequencies shown are normalized per 10,000 tags (column SHEP-2 and SHEP-21N). The column “ratio ON:OFF” shows the fold induction (positive values) or suppression (negative values) by N-myc. When a tag had a zero expression in one of the libraries, it was assumed for ratio calculation that the tag was present one time in the entire library. The Unigene numbers of the National Center for Biotechnology Information (NCBI, Bethesda, USA) are given in the column “Unigene.” The numbers are based on the NCBI Unigene database as by 29-3-2000. The next column shows the Unigene description. Furthermore, for each Unigene cluster, one or two Genbank accession codes are given. For some tags, two possible corresponding genes were identified which is indicated by an asterisk in the column next to the tag.  
         [0100]    Table 2 lists tags that were identified to differ significantly (p&lt;0.01) between the SAGE libraries of SHEP-2 and SHEP-21N after extending the sequencing of library SHEP-21N from 21,559 tags to 34,426 tags. Table 2 lists expression levels in both libraries expressed per 20,000 transcript tags (column “SHEP-2” and “SHEP-21N”), the unigene number as identified by the computer program described by Caron et al. (2001) and in some cases a Genbank accession number of a clone corresponding to the Unigene cluster.  
         [0101]    Experimental Procedures.  
         [0102]    Cell Lines.  
         [0103]    Neuroblastoma cell lines and culture conditions were as described (Cheng et al., 1995). The melanoma cell lines IGR39D and clone 3 were described by Versteeg et al. (1988). The SHEP cell lines were maintained in RPMI 1640 medium supplemented with 10% fetal calf serum, 4 mM L-glutamine, 100 U/ml penicillin and 100 μg/ml streptomycin (Lutz et al., 1996). Tetracycline (Sigma) was used at a concentration of 10 ng/ml medium to inhibit N-myc expression.  
         [0104]    Generation of SAGE Libraries.  
         [0105]    SAGE was performed as described by Velculescu et al. (1995) with a few adaptations. Total RNA was extracted by guanidium thiocyanate (Chromczynski and Sacchi, 1987). Poly(A) +  RNA was isolated using the MessageMaker kit (Gibco/BRL) according to the manufacturer&#39;s instructions. SAGE libraries were generated using minimally 4 μg poly(A) +  RNA. The cDNA was synthesized according to the Superscript Choice System (Gibco/BRL), digested with NlaIII and bound to streptavidin-coated magnetic beads (Dynal). Linkers containing recognition sites for BsmFI were ligated to the cDNA. Linker tags including a cDNA tag were released by BsmFI digestion, ligated to one another and amplified. The PCR products were heated for 5 minutes at 65° C. before preparative analysis on a polyacrylamide gel. After the ligation into concatameres, a second heating step was included (15 minutes at 65° C.) and fragments between 800 bp and 1500 bp were purified and cloned in pZero-1 (Invitrogen). Colonies were screened with PCR using M13 forward and reverse primers. Inserts larger than 300 bp were sequenced with a BigDye terminator kit and analyzed on a 377 ABI automated sequencer (Perkin Elmer).  
         [0106]    Analysis SAGE Database.  
         [0107]    The SAGE libraries were analyzed using the SAGE 300 program software package (Velsculescu et al., 1997). P-values were calculated using Monte Carlo simulations. Transcripts were identified by comparison of the tags in the database with the “tag to gene map” (SAGEmap) from Cancer Genome Anatomy Project available from NCBI. This database links Unigene clusters to SAGE tags (Lal et al., 1999). The gene assignments were subsequently checked by hand or sequencing errors causing incorrect tags and for erroneous gene assignments based on hybrid Unigene clusters. Other database analysis and generation of specific primers utilized the Wisconsin GCG package software.  
         [0108]    Northern Blot Analysis.  
         [0109]    Total RNA (20 μg per lane) was electrophoresed through a 0.8% agarose gel in the presence of 6.7% formaldehyde and blotted on Hybond N membranes (Amersham) in 10×SSC. Hybridization was carried out overnight in 0.5 M NaHPO 4 , pH 7.0, 7% SOS, 1 mM EDTA at 65° C. Filters were washed in 40 mM NaHPO 4 , 1% SDS at 65° C. Probes were labelled by random priming of sequence-verified PCR products.  
         [0110]    Total Protein Content.  
         [0111]    Exponentially growing cells were harvested and the number of cells was determined using a Coulter counter. Cells (1×10 6 ) were lysed in 20 mM Tris-HCl (pH 8.0), 137 mM NaCl, 10% glycerol, 1% NP40 and protease inhibitors (protease cocktail, Roche). Samples were assayed with the Bio-Rad Protein assay. Assays were performed at least in duplicate.  
         [0112]    Western Blots.  
         [0113]    Cell lysates were separated on SDS-polyacrylamide gel and electroblotted onto Immobilon-P transfer membrane (Millipore). Blocking of the membrane and incubation with antibodies involved standard procedures. Proteins were visualized using the ECL detection system (Amersham). Anti-nucleophosmin monoclonal antibody was a gift of Dr. P. K. Chan (Baylor College of Medicine). The antibody against nucleolin was a gift of Dr. P. Bouvet (CNRS, IPBS, Toulouse, France). Anti-N-myc was obtained from PharmIngen (Clone B8.4.B).  
         [0114]    Total rRNA Content.  
         [0115]    Total RNA of 1×10 6  exponentially growing cells was extracted by guanidium isothiocyanate (Chromczynski and Sacchi, 1987) and photospectrometrically quantified. Results of ten isolations of each of the cell lines SHEP-2 and SHEP-21N were statistically analyzed with the Students T test for independent samples. Aliquots on a per cell basis were subjected to agarose gel electrophoresis and stained with ethidium bromide. The relative fluorescence of the rRNA bands was quantified using the Kodak Digital Science  10  Image Analysis Software package (EDAS 120).  
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                                                         TABLE 1                       MYCN regulated genes (grouped by functional category)                                                                RIBOSOMAL PROTEINS                                           47.7   0.000   0.0   10.7   5174   ribosomal protein S17   AA876041, AI564812,                                       43.5   0.000   0.0   9.7   180920   ribosomal protein S9   AI064904, U14971                                       38.3   0.000   0.4   17.2   82148   ribosomal protein S12   AA483128, AA524764,                                       29.0   0.000   0.2   6.5   75458   ribosomal protein L18   L11566, AA513721,                                       26.9   0.000   0.2   6.0   178391   L44-         ribosomal protein (L44L),  Homo sapiens  Brutants tyrosine kinase (BTK), alpha-D-gal   W05120, AA181201,                                       20.7   0.000   0.7   13.9   8102   ribosomal protein S20   AI741190, AA064902,                                       16.6   0.000   0.4   7.4   165590   ribosomal protein S13   AI350382, AI290903,                                       16.6   0.000   0.9   14.8   80617   ribosomal protein S16   AI262558, AA628078,                                       12.4   0.006   0.2   2.8   3254   ribosomal protein L23-like   U26596, Z49254,                                   *   12.4   0.006   0.2   2.8   1948   ribosomal protein S21   AW196629                                       12.4   0.000   0.7   8.3   179666   ribosomal protein L35a   AW328435, AW328458,                                       11.4   0.000   0.4   5.1   74267   ribosomal protein L15   AW327407, AA689521,                                       11.4   0.000   1.3   15.3   73742   ribosomal protein, large, P0   AA807754, AI174682,                                       11.0   0.000   3.1   34.3   182426   ribosomal protein S2   X17206, AA704039,                                       9.9   0.000   2.2   22.3   178551   ribosomal protein L8   AW327732, AI200056,                                       9.2   0.000   1.6   14.4   153177   ribosomal protein S28   AA229774, AA421061,                                   *   8.3   0.010   0.0   1.9   128400   ESTs, Highly similar to 60S RIBOSOMAL PROTEIN L39 [ H. sapiens ]   AA075869                                       8.0   0.000   1.6   12.5   180450   ribosomal protein S24   AW410149, D51704,                                       7.7   0.000   2.2   17.2   75362   ribosomal protein S18   AA178543, AW409851,                                       7.4   0.000   1.6   11.6   2017   ribosomal protein L38   AA659304, AA747113,                                       7.1   0.000   1.6   11.1   91379   ribosomal protein L26   AA084377, AA111974,                                       6.6   0.000   1.1   7.4   99914   ribosomal protein L22   AA420829, AA603500,                                       6.0   0.000   1.8   10.7   157850   ribosomal protein L9   D14531, U09953,                                       5.9   0.000   3.1   18.6   182825   ribosomal protein L35   AA457581, AA479946,                                       5.9   0.000   2.7   15.8   119598   ribosomal protein L3   AA121930, AW022183,                                       5.7   0.002   0.9   5.1   158675   ribosomal protein L14   AA857488, AA186408,                                       5.7   0.000   8.3   46.8   163698   ribosomal protein L29   U10248, U49083,                                       5.3   0.000   4.9   26.0   163593   ribosomal protein L18a   AI719134, AA047273,                                       5.2   0.000   4.0   20.9   195453   ribosomal protein S27 (metallopanstimulin 1)   AA525023, AA555149,                                       5.1   0.000   2.5   12.5   252259   ribosomal protein S3   AA708649, AI792490,                                       4.8   0.000   2.0   9.7   75538   ribosomal protein S7   M77233, AA513485,                                       4.7   0.000   2.7   12.5   177415   ribosomal protein S30; Finkel-Biskis-         murine sarcoma virus (FBR-MuSV)              AA025263, AA055838,                                       4.7   0.000   1.8   8.3   75879   ribosomal protein L19   AI219423, AA075993,                                       4.6   0.000   2.2   10.2   180946   ribosomal protein L5   W95798, AA491764,                                   *   4.3   0.000   21.5   91.4   151004   ribosomal protein S8   AI357743, AW051118,                                       4.1   0.000   5.4   22.3                 ribosomal protein L28   AA225838, AA480489,                                       4.0   0.000   3.1   12.5   184014   ribosomal protein L31   AA340384, AA024502,                                       4.0   0.000   7.6   30.1   180842   ribosomal protein L13   AI808885, AI992115,       39   CTGTTGGTGA       3.9   0.000   4.0   15.8   3463   ribosomal protein S23   AW020385, AW022474,       40   AGGGCTTCCA       3.8   0.000   5.1   19.5   29797   ribosomal protein L10   AA244126, AA508388,       41   TAAGGAGCTG       3.8   0.000   3.8   14.4   77904   ribosomal protein S26   AW022428, X69654,       42   GTGAAGGCAG       3.7   0.000   3.4   12.5   77039   ribosomal protein S3A   AA070817, AA074191,       43   CGCCGGAACA       3.4   0.000   3.8   13.0   286   ribosomal protein L4   AL119264, AW021149,       44   AGGCTACGGA       3.4   0.000   8.7   29.7   119122   ribosomal protein L13a   AA190354, AW328422,       45   CCTTCGAGAT       3.3   0.000   4.0   13.5   76194   ribosomal protein S5   AI971757, AA057826,       46   AAGACAGTGG       3.3   0.000   9.2   30.1   184109   ribosomal protein L37a   AA353060, AW020311,       47   TTACCATATC       3.3   0.000   6.9   22.7   177461   ribosomal protein L39   AW023657, T40220,       48   TGTGCTAAAT       3.2   0.000   5.1   16.7   250695   ribosomal protein L34   AW020881, N85940,       49   GCCGTGTCCG       3.2   0.001   2.9   9.3   241507   ribosomal protein S6   AA148286, AA167421,       50   GGCAAGAAGA       3.0   0.000   3.8   11.6   111611   ribosomal protein L27   AA531226,          ,       51   ACATCATCGA       3.0   0.000   7.4   22.3   182979   ribosomal protein L12   L06505, AA484263,       52   GGATTTGGCC       2.9   0.000   16.8   48.2   251247   ribosomal protein, large P2   AA037465, AA064832,       53   CGCTGGTTCC       2.8   0.000   8.5   24.1   179943   ribosomal protein L11   AA226392, AA230322,       54   TACAAGAGGA       2.8   0.006   2.7   7.4   174131   ribosomal protein L6   AI042168, D17554       55   TTGGTCCTCT       2.7   0.000   18.4   50.1   108124   ribosomal protein L41   Z12962, AA045319,       56   CTCCTCACCT       2.6   0.001   4.9   13.0   119122   ribosomal protein L13a   AW242158, AW245640,       57   AATAGGTCCA       2.5   0.000   9.2   23.2   113029   ribosomal protein S25   AA228780, AA229897,       58   GAGGGAGTTT       2.5   0.000   18.6   46.8   76064   ribosomal protein L27a   AA228189, AA229949,       59   AAGAAGATAG       2.5   0.002   4.3   10.7   184776   ribosomal protein L23a   AA040728, AA888884,       60   ATTATTTTTC       2.5   0.006   3.6   8.8   153   ribosomal protein L7   AA138446, AW020191,       61   ACTCCAAAAA       2.2   0.000   10.3   22.7   133230   ribosomal protein S15   AA079663, AA151459,           SECTION 2.                           PROTEIN SYNTHESIS       62   CTGGCGAGCG       18.6   0.000   0.2   4.2   174070             carrier protein   AA211097, AA283711,       63   GAGCGGGATG       16.6   0.001   0.2   3.7   77080   proteasome (prosome, macropain) subunit beta type, 6   D29012, X61971,       64   GCATAGGCTG       12.4   0.000   0.4   5.6   12084   Tu translation elongation factor, mitochondrial   AL037768, L38995,       65   GGCTCCCACT       11.7   0.000   0.7   7.9   74335   heat shock 90 kD protein 1, beta   AW023752, AA034511,       66   GCCCAGCTGG       11.4   0.000   0.4   5.1   223241   eukaryotic translation elongation factor 1 delta (guanine nucleotide exchange protein)   Z21507, AA489523,       67   TGAAATAAAC   *   10.4   0.004   0.0   2.3   173205   nucleophosmin (nucleolar phosphoprotein B23, numatin)   AI184619       68   TACCAGTGTA       10.4   0.004   0.0   2.3   79037   heat shock 60 kD protein 1 (chaperonin)   AW021205, AW103323,       69   TGTGTTGAGA       9.4   0.000   5.6   52.4   181165   eukaryotic translation elongation factor 1 alpha 1   AA630271, AA668532,       70   TGGGCAAAGC       9.0   0.000   2.0   18.1   2188   eukaryotic translation elongation factor 1 gamma   AA038923, AA190762,       71   ACATCCTCAC       8.3   0.010   0.0   1.9   18700   proteasome (prosome, macropain) 26S subunit, non-ATPase, 13   AA024838, AA149127,       72   TAAAATTTGT   *   8.3   0.010   0.0   1.9   93379   eukaryofic translation initiation factor 4B   AA054750, AA133563,       73   CAGTCTAAAA       8.3   0.003   0.4   3.7   76118   ubiquitin carboxyl-terminal esterase L1 (         thiolesterase)   X04741, AA029783,       74   GAAGGCATCC       8.3   0.010   0.0   1.9   250758   proteasome (prosome, macropain) 28S subunit, ATPase, 3   F32284, AA130329,       75   TGGCTAGTGT       6.9   0.001   0.7   4.6   118865   proteasome (prosome, macropain) subunit, beta type, 7   AA804284, AA829376,       76   CAGATCTTTG       5.8   0.000   1.1   6.5                 ubiquitin A-52 residue ribosomal protein fusion product 1   AF075321, AI110823,       77   TCACAAGCAA       4.4   0.001   1.6   7.0   146763   nascent-polypeptide-associated complex alpha polypeptide   AF054187, X80909,       78   AACTCTTGAA       3.6   0.006   1.3   5.1   58189   eukaryotic translation initiation factor 3, subunit 3 (gamma, 40 kD)   U54559, AA024720,       79   AGCACCTCCA       3.5   0.000   9.0   31.5   75309   eukaryotic translation elongation factor 2   AA229607, AA533837,       80   AGCCCTACAA   *   3.4   0.000   15.4   52.9   180532   heat shock 90 kD protein 1, alpha   AW088888, AW128905,       81   CGCCGCGGTG       2.9   0.004   2.7   7.9   4835   eukaryotic translation initiation factor 3, subunit 8 (110 kD)   AA573953, AA778265,       82   TTCATACACC   *   2.6   0.000   31.3   82.8   180532   heat shock 90 kD protein 1, alpha   AW080984       83   TGAAATAAAA       2.5   0.000   10.1   25.5   173205   nucleophosmin (nucleolar phosphoprotein B23, numatrin)   AI926288, AW166350,       84   ATCAGTGGCT       2.5   0.009   3.1   7.9   89545   proteasome (prosome, macropain) subunit, beta type, 4   R25997, R68878,       85   CCCTGATTTT       −7.1   0.000   9.8   1.4   183684   eukaryotic translation initiation factor 4 gamma, 2   U73824, U76111,       86   AAGAGGTTTG       −9.2   0.001   4.3   0.0   74368   transmembrane protein (63 kD), endoplasmic reticulum/Golgi intermediate compartment   X69910, AI131495,       87   GTTTTTGCTT       2.4   0.075   1.6   3.7   79110   Nucleolin   AA133588, AA135423, A       88   TACAAAACCA       2.1   0.923   0.9   1.9   79110   Nucleolin   AA088423, AA284953, A           SECTION 3.                           GENES INVOLVED IN METASTASIS       89   AATAGAAATT       14.5   0.000   0.0   3.2   313   secreted phosphoprotein 1 (osteopontin, bone sialoprotein 1, early T-lymphocyte activation 1)   AW021049, AA021512,       90   ATGCTCCCTG       14.5   0.000   0.0   3.2   79339   lactin, galactoside-binding, soluble, 3 binding protein (galectin 6 binding protein)   L13210, X79089       91   ACAGGGTGAC       14.5   0.000   0.0   3.2   174050   endothelial differentiation-related factor 1   AA975055, AA992919,       92   AACGCGGCCA       12.8   0.000   1.1   14.4   73798   macrophage migration inhibitory factor (glycosylation-inhibiting factor)   AA523321, AA927264       93   AAGAAAGGAG       11.4   0.000   0.9   10.2   202097   procollagen C-endopeptidase enhancer   L33799       94   GTAAGTCTCA       8.3   0.010   0.0   1.9   211584   neurofilament, light polypeptide (68 kD)   AW022557, AA330627,       95   GCCGATCCTC       8.3   0.010   0.0   1.9   24930   tubulin-specific chaperone a   AF038952       96   GGCTCCTGGC       8.3   0.010   0.0   1.9   5215   integrin beta 4 binding protein   AF022229, AF047433,       97   GCCGGGTGGG       7.8   0.001   0.7   5.1   74631   basigin   D45131, L10240,       98   GGGGAAATCG       5.9   0.000   3.8   22.3   76293   thymosin, beta 1D   AA147288, AA155816,       99   GCCCCCAATA       −1.7   0.007   20.1   11.6   227751   lectin, galactoside-binding, soluble, 1 (galectin 1)   J04456, X14829,       100   ACCAAAAACC       −1.8   0.003   21.3   11.6   172928   collagen, type I, alpha 1   AA454809, AA454820,       101   GTTGTGGTTA       −2.2   0.000   30.0   13.9   75415   beta-2-microglobulin   AB021288, AA897072,       102   AACTGCTTCA       −2.5   0.002   12.8   5.1   11538   actin related protein 2/3 complex, subunit fB (41 kD)   AA031434, AA045773,       103   TCTCTGATGC       −2.7   0.001   12.5   4.6   6441   tissue inhibitor of                    2   AL110197, AL134962,       104   TGTACCTGTA       −2.8   0.000   14.1   5.1   169478   tubulin, alpha, ubiquitous   AA018607, AA018627,       105   GCTTTATTTG       −2.9   0.000   15.9   5.6   180952   actin, beta   AA419273, AA528145,       106   TCCTGTAAAG       −3.1   0.007   7.2   2.3   74034   caveolin 1, caveolae protein, 22 kD   AA034380, AA044994,       107   TGCTAAAAAA       −4.7   0.000   17.5   3.7   146550   myosin, heavy polypeptide 9, non-muscle   AA041529, AA070528,       108   TGGAAATGAC       −4.9   0.000   42.8   8.8   172928   collagen, type I, alpha 1   AA853342, AA436411,       109   TGGAAATGCC       −5.0   0.001   6.9   1.4   172928   collagen, type I, alpha 1   AI190987, AI339782,       110   GTTTTTTTTA   *   −5.5   0.004   5.1   0.9   179573   collagen, type I, alpha 2   AI825593       111   ACAGGCTACG       −6.0   0.002   5.6   0.9   75777                 AI188763, AI540294,       112   TAAAAATGTT       −6.3   0.000   17.5   2.8   82085   plasminogen activator inhibitor, type I   M14083, AA040151,       113   GTTTCTAATA       −6.3   0.006   2.9   0.0   239298   microtubule-associated protein 4   AA043400, AA086286,       114   TTAAAGATTT       −7.1   0.000   13.2   1.9   77899   tropomyosin 1 (alpha)   AA026364, AA036782,       115   GACCGCAGGA       −7.2   0.003   3.4   0.0   119129   collagen, type IV, alpha 1   X03883, AW020005,       116   TAATCCTCAA       −8.2   0.000   7.6   0.9   78409   collagen, type XVIII, alpha 1   AA009987, AA099281,       117   TGTAGAAAAA       −9.2   0.004   4.3   0.5   119076   tubulin, beta polypeptide                       , AI623884,       118   TTAGTGTCGT       −10.6   0.002   4.9   0.5   111779   secreted protein, acidic, cystaine-rich (osleonectin)   AW020585, AW022769,       119   GCCCCAATAA   *   −11.1   0.000   5.1   0.0   227751   lectin, galactoside-binding, soluble, 1 (galectin I)   AA095630       120   AAAGTCATTG   *   −11.1   0.001   5.1   0.5   77899   tropomyosin 1 (alpha)   M19713       121   TGCAATATGC       −12.5   0.000   5.8   0.0   750   fibrillin 1 (Marian syndrome)   L13923, X63556,       122   ATCTTGTTAC       −14.5   0.000   6.7   0.5   116162   fibronectin 1   AW020421, AW020447,       123   AAAAAGCTGC       −15.9   0.000   7.4   0.0   111779   secreted protein, acidic, cysteine-rich (osteonectin)   AA987875, AI755199,       124   AAAATATTTT       −18.8   0.000   8.7   0.0   119000   actinin, alpha 1   X55187, AA024895,       125   ATGTGAAGAG       −19.9   0.000   268.2   13.5   111779   secreted protein, acidic, cysteine-rich (osteonectin)   AA228362, AA852763,       126   TGGCCTAATA       −27.5   0.000   12.8   0.0   1501   syndecan 2 (heparan sulfate proteoglycan 1, cell surface-associated, fibroglycan)   AA873519, AI279414,       127   TTTGCACCTT       −37.6   0.000   17.5   0.5   75511   connective tissue growth factor   AW021964, U14750,           SECTION 4.                           GLYCOLYSIS ENZYMES       128   TAGCTTCTTC       14.5   0.000   0.0   3.2   76392   aldehyde dehydrogenase 1, soluble   AA911018, AI150648,       129   ACCTTGTGCC       10.4   0.004   0.0   2.3   878   sorbitol dehydrogenase   AA570172, AA570189,       130   TCTGCTTGTC       10.4   0.004   0.0   2.3   76392   aldehyde dehydrogenase 1, soluble   H79748, H05271,       131   TGACTGAAGC       10.4   0.004   0.0   2.3   3343   3-phosphoglycerate dehydrogenase   AA742550, AA113268,       132   TGGCCCCACC       7.5   0.000   1.1   8.3   198281   pyruvate kinase, muscle   AA766601, AA768285,       133   GCGACCGTCA       7.3   0.000   0.9   6.5   183760   aldolase A, fructose-bisphosphate   AA169762, AA557193,       134   TACCATCAAT       4.7   0.000   5.8   27.4   195188   glyceraldehyde-3-phosphate dehydrogenase   AA226658, AA522734,       135   TGAGGGAATA       4.4   0.000   2.2   9.7   83848   triosephosphate isomerase 1   AA587096, AA587188,           SECTION 5.                           MITOCHONDRIAL FUNCTION PROTEINS       136   GAATCGGTTA       22.8   0.000   0.2   5.1   80595   NADH dehydrogenase (ubiquinone) Fe-S protein 5 (15 kD) (NDUFB4)   AF047434, AA457600,       137   GGGGGTCACC       18.6   0.000   0.0   4.2   80986   ATP synthase, H+ transporting, mitochondrial F0 complex, subunit c (subunit 9), isoform 1   AA659764, AA866065,       138   AAGGAGTTTG       14.5   0.000   0.0   3.2   661   NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 7 (18 kD, B18)   AA493442, AA832435,       139   AGGTCCTAGC       14.5   0.000   0.4   6.5   226795   glutathione S-transferase pi   F34719, U30897,       140   CTTAGAGCCC       12.4   0.006   0.2   2.8   211929   thioredoxin, mitochondrial   AI680239       141   TTCTGGCTGC       12.4   0.006   0.2   2.8   119251   ubiquinol-cytochrome c reductase core protein 1   F28971, AI005342,       142   GTGGTACAGG       7.3   0.007   0.4   3.2   31731   ESTs, Highly similar to PUTATIVE PEROXISOMAL ANTIOXIDANT ENZYME [ H. sapiens ]   AA745952, AA829707,       143   GTGACAACAC       5.2   0.003   0.9   4.6   149155   voltage-dependent anion channel 1   AA907238, AI075271,       144   GCCTGCTGGG       4.8   0.000   2.0   9.7                 glutathione peroxidase 4 (phospholipid hydroperoxidase)   X71973, AA743017,       145   GGGGACTGAA       4.6   0.003   1.1   5.1   3709   low molecular mass ubiquinone-binding protein (9.5 kD)   AA010879, AA025093,       146   CCCATCGTCC   *   4.3   0.000   21.5   91.4   mito   cytochrome c oxidase II (Welle et al., 1999), Tag matches mitochondrial sequences   AA069405, AA074137       147   TGATTTCACT   *   4.1   0.000   4.0   18.7   mito   cytochrome c oxidase III (Welle et al., 1999), Tag matches mitochondrial sequences   AA757623       148   TGAAGGAGCC       4.1   0.007   1.1   4.6   89399   ATP synthase, H+ transporting, mitochondrial F0 complex, subunit c (subunit 9), isoform 2   F27013, D13119,       149   GTGACCTCCT       4.1   0.003   1.3   5.6   81097   cytochrome c oxidase subunit VIII   F28051, F28676,       150   AGCCCTACAA   *   3.4   0.000   15.4   52.9   mito   NADH dehydrogenase 3 (Welle et al., 1999), Tag matches mitochondrial sequences   AA577697, AI022799       151   TTCATACACC   *   2.6   0.000   31.3   82.6   mito   NADH dehydrogenase 4/4L (Welle et al., 1999), Tag matches mitochondrial sequences   AA971178       152   CACCTAATTG   *   2.3   0.000   34.2   79.3   mito   ATPase 6/8 (Welle et al., 1999), Tag matches mitochondrial sequences   AA031407       153   GAGAGCTCCC       −2.6   0.008   7.8   2.8   169919   electron-transfer-flavoprotein, alpha polypeptide (glutaric aciduria II)   AI364921       154   GTAAGATTAG   *   −5.8   0.000   8.1   1.4   5417   oxygen regulated protein (150 kD)   AA828743       155   GCCCCAATAA   *   −11.1   0.000   5.1   0.0   173554   ubiquinol-cytochrome c reductase core protein II   AA425586           SECTION 6.                           OTHER GENES       156   CCCCCTGGAT       21.8   0.000   0.4   9.7   N/A   calcyclin   AI832624, AA081048,       157   GTGCGCTAGG       18.6   0.000   0.2   4.2   9408   ESTs, classified Into serine/threonine kinase, Highly similar to The KIAA0151 gene product is   AA420781, AA492367,       158   GAGTGGGGGC       18.6   0.000   0.2   4.2   14089   ESTs, Weakly similar to LYSOSOMAL PRO-X CARBOXYPEPTIDASE PRECURSOR [H.s   AA362125, AA418395,       159   TTTCCTTCCT   *   16.6   0.001   0.2   3.7   104143                       , light polypeptide (Lca)   AA574409, AA737504,       160   ATAAGATACA       16.6   0.000   0.0   3.7   199026   RAS p21 protein activator (GTPase activating protein) 3 (Ins(1,3,4,5)P4-binding protein)   X69399       161   AACGCTGCCT       14.5   0.000   0.0   3.2   28914   adenine phosphoribosyltransferase   AA444001, AA535523       162   ATTTGTCCCA       12.4   0.000   0.4   5.6   139800   high-mobility group (nonhistone chromosomal) protein Isoforms I and Y   AA071304, AA074087,       163   TCAGACGCAG       12.4   0.006   0.2   2.8   182371   prothymosin, alpha (gene sequence 28)   AW129309       164   TCTCTTTTTC   *   12.4   0.006   0.2   2.8   119529   epididymal secretory protein (19.5 kD)   AA025798, AA039545,       165   TTTCAGGGGA   *   12.4   0.006   0.2   2.8   2853   poly(rC)-binding protein 1   AI312897       166   CGGCCCAACG       12.4   0.001   0.0   2.8   20521   HMTI (hnRNP methyltransferase, S, cerevisiae)-like 2   AA031375, AA187773,       167   TTCTCCCGCT       12.4   0.001   0.0   2.8   118126   protective protein for beta-galactosidase (galactosalidosis)   M22960, AI752680,       168   GGGGGACGGC       12.4   0.001   0.0   2.8   21346   ESTs, Weakly similar to F42C5.7 gene product ( C. elegans )   AA015864, AA026165,       169   GGCCCTGAGC       11.4   0.000   0.4   5.1   71618   polymerase (RNA) II (DNA directed) polypeptide L (7.6 kD), Human RNA polymerase II subu   AA570105, AA562657,       170   TATGTGATTT       10.4   0.000   0.4   4.6   5216   ESTs, Highly similar to HSPC028 [ H. sapiens ]   AA713577, AA748622,       171   GGCAGAGGAC       10.4   0.000   0.7   7.0   118638   non-metastatic cells 1, protein (NM23A) expressed in   X17620, AA046312,       172   GCCAAGATGC       10.4   0.004   0.0   2.3   83135   p53-responsive gene 6   AA038471, AA149617,       173   CCCACACTAC       10.4   0.004   0.0   2.3   242024   guanine nucleotide binding protein (G protein), beta polypeptide 2   M16538, AA548194,       174   CCGTCATCCT       10.4   0.004   0.0   2.3   153591   Not56 (D. melanogaster)-like protein   AI914552, AA412507,       175   TGAAATAAAC   *   10.4   0.004   0.0   2.3   155212   methylmalonyl Coenzyme A mutase   AI569812, AI628986,       176   TGAAATAAAC   *   10.4   0.004   0.0   2.3   238380   Human endogenous retroviral protease mRNA, complete cds   AA527289       177   GACCCTGCCC       10.4   0.004   0.0   2.3   173464   FK506-binding protein 8 (38 kD)   L37033, AA587607,       178   CAGCAGAAGC       9.8   0.000   0.9   8.8   256313   pinin, desmosome associated protein   N76807       179   CTCATAGCAG   *   9.3   0.001   0.4   4.2   103636   chromosome 1 open reading frame 9   AI312752, AI312755       180   CTCATAGCAG   *   9.3   0.001   0.4   4.2   119252   tumor protein, translationally-controlled 1   N92214, AA045631,       181   CTGGGCCTGG       8.3   0.010   0.0   1.9   74573   similar to vaccinia virus                    KAL ORF   N99342, D45708,       182   GGGGTAAGAA       8.3   0.010   0.0   1.9   80423   prostatic binding protein   AA613924, AA825254,       183   GGGCTGGGCC       8.3   0.010   0.0   1.9   100071   6-phosphogluconolactonase   AI217069, AI279087,       184   TTTTTTGTAA       8.3   0.010   0.0   1.9   97858   SH3-domain binding protein 1   AA748769       185   GCAGTGGCCT       8.3   0.010   0.0   1.9   184276   solute carrier family 9 (sodium/hydrogen exchanger), Isoform 3 regulatory factor 1   AA425299, AA593621,       186   CCCCCAATGC       8.3   0.010   0.0   1.9   115232   Spliceosome protein SAP-62   AI280056, AI348200,       187   CTGCTGTGAT   *   8.3   0.010   0.0   1.9   1063   small nuclear                    polypeptide C   AA089406, AA099919,       188   CAGTTGGTTG       8.3   0.010   0.0   1.9   155218   E1B-55 kDa-associated protein 5   AA130531, AA155800,       189   ATCCATAGTG       8.3   0.010   0.0   1.9   66772   TATA box binding protein (TBP)-associated factor, RNA polymerase II, N, 68 kD (RNA-             AA662359, AA857343,       190   CTGGATGCCG       8.3   0.010   0.0   1.9   106061   RD RNA-binding protein   AA569818, AA988602,       191   CTGACCCCCT       8.3   0.010   0.0   1.9   26492   beta-1,3-                   3 (glucuronosyltransferase I)   AB009598, AJ005865,       192   CCTGTACCCC   *   8.3   0.010   0.0   1.9   32317   Sox-like transcriptional factor   AA045957, AA196459,       193   TAAAATTTGT   *   8.3   0.010   0.0   1.9   32317   Sox-like transcriptional factor   AA919117       194   TGGCCTGCCC       8.3   0.010   0.0   1.9   181002   MLL septin-like fusion   AA761307, AA831791,       195   TGGCCTCCCC       8.3   0.010   0.0   1.9   159161   Rho GDP dissociation Inhibitor (GDI) alpha   X69550       196   TGCAGCGCCT       8.3   0.010   0.0   1.9   77573                       phosphorylase   X90858, AI018589,       197   TGAGGGGTGA       8.3   0.010   0.0   1.9   252979   G protein pathway                    1   AA521025, AA569807,       198   TGAGGCCAGG   *   8.3   0.010   0.0   1.9   79162   structure specific recognition protein 1   AW328290, M86737,       199   GAGAGAAGAG       8.3   0.010   0.0   1.9   13476   UDP-GalbetaGlcNAc beta 1,4-galactosyltransferase, polypeptide 3   AA721091, AA743639,       200   TCTTCTCACA   *   8.3   0.010   0.0   1.9   656   cell division cycle 25C   AA206499, AA534482,       201   GCCGCTACTT       8.3   0.010   0.0   1.9   32989                       receptor-like receptor activity modifying protein 1   AI951585, AJ001014       202   CCCTCCTCCG       8.3   0.010   0.0   1.9   81131   guanidinoacetate N-methyltransferase   D59710, AI123221,       203   TATGACCACA   *   8.3   0.010   0.0   1.9   6650   vacuolar protein sorting 45B (yeast homolog)   AA765898, AA769317,       204   TACATTCACC       8.3   0.010   0.0   1.9   82043   D123 gene product   D14876, U27112,       205   AAGCGGGACC       8.3   0.010   0.0   1.9   153438   N-acetyltransferase, homolog of  S. cerevisiae  ARD1   X77588, AA158247,       206   GATCAATGGA   *   8.3   0.010   0.0   1.9   3090   EphB1   AA449788, AA640161,       207   GATCAATGGA   *   8.3   0.010   0.0   1.9   251788   glucosamine-6-phosphate deaminase   AA031910, AA151768,       208   GCCGCCATCT       8.3   0.010   0.0   1.9   89643                       (                   -Korsakoff syndrome)   U55017       209   CCCTGGGTTC       7.7   0.000   2.5   19.0   111334   ferritin, light polypeptide   M11147, M12938,       210   CAGCCTTGGA       7.3   0.007   0.4   3.2   65648   RNA binding motif protein 8   AA045586, AA188655,       211   ACCCTTCCCT   *   7.3   0.007   0.4   3.2   99528   ESTs, Weakly similar to VON EBNER&#39;S GLAND PROTEIN PRECURSOR [ H. sapiens ]   AA936288, AA977608,       212   GAGGGGAAAC       7.3   0.007   0.4   3.2   81972   SHC (Src homology 2 domain-containing) transforming protein 1   AA767918, X68148,       213   ACCCTTCCCT   *   7.3   0.007   0.4   3.2   74564   signal sequence receptor, beta (translocon-associated protein beta)   AW024384, D37991,       214   ACTGGGTCTA       6.5   0.000   1.6   10.2   250871   non-metastatic cells 2, protein (NM23B) expressed in   AA514798, AA828464,       215   TGGAGTGGAG       5.8   0.000   1.1   6.5   3764   guanylate kinase 1   F25667, AA024959,       216   CCCCTCCCTC   *   5.5   0.008   0.7   3.7   79410   solute carrier family 4, anion exchanger, member 2 (erythrocyte membrane protein band 3-             AA741103, AA767203,       217   CCCCTCCCTC   *   6.5   0.008   0.7   3.7   74564   signal sequence receptor, beta (translocon-associated protein beta)   AW083845       218   ACAGTGGGGA       4.6   0.003   1.1   5.1   75839   zinc finger protein 6 (CMPX1)   AA740738, AA100363,       219   TGATTTCACT   *   4.1   0.000   4.0   16.7   24322   ATPase, H+ transporting, lysosomal (vacuolar proton pump) 9 kD   AI065143       220   TTATGGGATC       4.0   0.000   3.4   13.5   5862   guanine nucleotide binding protein (G protein), beta polypeptide 2-like 1   M24194, AA480431,       221   ATAGACATAA       2.8   0.007   2.5   7.0                 complement component 1, q subcomponent binding protein   AI916184, AA195312,       222   CACCTAATTG   *   2.3   0.000   34.2   79.3   181368   U5 anRNP-specific protein (220 kD), ortholog of  S. cerevisiae  Prp8p   AW129234, AW151854,       223   GAAATACAGT   *   −1.8   0.006   18.6   10.2   79572   cathepain D (lysosomal aspartyl protease)   AA046688, AA063376,       224   GCCTTCCAAT       −2.0   0.004   15.9   7.9   76053   DEAD/H (Asp-Glu-Ala-Asp/His) box polypeptide 5 (RNA helicase, 68 kD)   AA030969, AW019938,       225   GTGTGTTTGT       −2.0   0.005   15.0   7.4   118787   transforming growth factor, beta-induced, 68 kD   M77349, AW021500,       226   AGCAGATCAG       −2.2   0.004   13.2   6.0   119301   S100 calcium-binding protein A10 (annexin II ligand, calpactin I, light polypeptide (p11))   AW022967, AA009605,       227   CTGCCAAGTT       −2.6   0.003   10.3   3.7   75873   zyxin   AA040172, AA054721,       228   TTCTGTGAAT   *   −3.7   0.002   8.5   2.3   182183   caldesmon 1   AA552208, AA652809,       229   CTTAATCCTG       −4.1   0.000   15.2   3.7   234433   ESTs, Weakly similar to transporter protein [ H. sapiens ]   AA864787, AW021494,       230   TCTCAATTCT   *   −4.5   0.003   6.3   1.4   173497   Sec23 (S.                    ) homolog B   AI581164, AW135796,       231   GCCCTTTCTC       −4.5   0.000   12.5   2.8   7835   endocytic receptor (macrophage mannose receptor family)   AA126747, AA405572,       232   TCTCAATTCT   *   −4.5   0.003   6.3   1.4   N/A   BB1   AA410935, AA022580,       233   TTCTTGTTTT       −5.3   0.006   4.9   0.9   74621   prion protein (p27-30) Creutzfeld-Jakob disease, Gertsmann-Strausler-Scheinker syndrome   D00015, M13687,       234   TATGACTTAA   *   −5.3   0.006   4.9   0.9   89230   potassium intermediate/small conductance calcium-activated channel, subfamily N, member   AA285078, AA491238,       235   GTTTTTTTTA   *   −5.5   0.004   5.1   0.9   10114   ESTs, Weakly similar to protein B [ H. sapiens ]   AA284721, AA496717,       236   GTCACAGTCC       −5.8   0.009   2.7   0.0   155321   serum response factor (c-los serum response element-binding transcription factor)   AA024483, AA041538,       237   TAAGAAAATG       −8.3   0.008   2.9   0.0   75929   cadherin 11 (OB-cadherin, osteoblast)   AA258422, AA461076,       238   TTTTTTAAAA       −6.3   0.006   2.9   0.0   227400   mitogen-activated protein kinase kinase kinase kinase 3   AA043537       239   TTACTTATAC   *   −6.8   0.004   3.1   0.0   159   tumor necrosis factor receptor superfamily, member 1A   AW138039       240   TTACTTATAC   *   −6.8   0.004   3.1   0.0                 wingless-type MMTV integration site family, member 2B   AW129457       241   GCTGTTTTGT       −6.8   0.004   3.1   0.0   92186   KIAA0989 protein   AB023206, AA405541,       242   CTTTCTTTGA       −8.2   0.001   3.8   0.0   4909   regulated in glioma   AF052161, AA209488,       243   AAAAGATACT       −8.2   0.009   3.8   0.5   82071   Cbp/p300-interacting transactivator, with Glu/Asp-rich carboxy-terminal domain, 2   AA115949, AA146987,       244   TCCGTGGTTG       −8.2   0.001   3.8   0.0   79516   brain acid-soluble protein 1   AF039656, AA602987,       245   CATTATAACT       −8.2   0.001   3.8   0.0   84359   hypothetical protein   AA806434, AA832337,       246   TGTCATCACA       −9.2   0.004   4.3   0.5   83354   lysyl oxidase-like 2   AA126278, AA149435,       247   TTTTGTTTTG   *   −9.7   0.003   4.5   0.5   95583                       4 superfamily member (tetraspan NET-7)   AA037844, AA040421,       248   TACAGAGGGA       −10.1   0.002   4.7   0.5   3776   zinc finger protein 216   AA730188, AA814563,       249   AAGTGAAACA       −11.1   0.001   5.1   0.5   93659   protein disulfide isomerase related protein (calcium-binding protein, intestinal-related)   AW411440       250   AGTTTCCCAA       −13.0   0.000   6.0   0.5   75854   SULT1C sulfotransferase   AF055584, AA113827,       251   TACAATAAAC       −14.0   0.000   6.5   0.0   9071   progesterone membrane binding protein   AA836144, AJ002030,       252   CATATCATTA       −15.9   0.000   7.4   0.0   119205   insulin-like growth factor binding protein 7                       ,                    ,           SECTION 7.                           EST clones of unknown function       253   GCACCTCAGC       14.5   0.000   0.0   3.2   10702   ESTs   AA027098, AA035781,       254   GAGAGAAAAT       14.5   0.000   0.0   3.2   181444   ESTs, Weakly similar to R12C12.6 [ C. elegans ]   AA476914, AA630706,       255   ACTTTTTAAA       14.1   0.000   1.1   15.8   157300   EST   AI365306       256   TTTCAGGGGA   *   12.4   0.006   0.2   2.8   3804   DKFZP564C1940 protein   AA831451, AA070917,       257   TGATGGGCAT       12.4   0.006   0.2   2.8   74284   ESTs, Moderately similar to  S. cerevisiae  hypothetical protein L3111 [ H. sapiens ]   AI688503, AI745361,       258   CTGGGCGTGT   *   12.4   0.001   0.0   2.8   108946   ESTs, Weakly similar to laminin beta-2 chain precursor [ H. sapiens ]   AA046403, AA759123,       259   ACGGTGATGT       12.4   0.001   0.0   2.8   10453   ESTs   AA005401, AA045808,       260   CTGGGCGTGT   *   12.4   0.001   0.0   2.8   15246   EST   T90794       261   TGAGGCCAGG   *   8.3   0.010   0.0   1.9   110128   ESTs   AA584364       262   GGTTTGTGTG       8.3   0.010   0.0   1.9   83954     Homo sapiens  unknown mRNA   AF061739, AA732389,       263   TTGTGGGATC       8.3   0.010   0.0   1.9   167795   ESTs   AA018907, AA126960,       264   CCTGTACCCC   *   6.3   0.010   0.0   1.9   12342     Homo sapiens  clone 24538 mRNA sequence   AI924428       265   TATGACCACA   *   6.3   0.010   0.0   1.9   176577   ESTs   AI651376       266   ACTACCTTCA       8.3   0.010   0.0   1.9   9601   ESTs, Highly similar to CGI-106 protein [ H. sapiens ]   AA744772, AA805690,       267   CTGCTGTGAT   *   8.3   0.010   0.0   1.9   193909   ESTs, Weakly similar to IIII ALU SUBFAMILY SC WARNING ENTRY IIII (H. sapiens)   AA628209, AJ690704,       268   GAGTGAGTGA   *   7.3   0.007   0.4   3.2   52186   ESTs, Weakly similar to IIII ALU SUBFAMILY J WARNING ENTRY IIII ( H. sapiens )   H62203       269   GAGTGAGTGA   *   7.3   0.007   0.4   3.2   10463   ESTs, Weakly similar to C44C1.2 gene product (C. elegans)   AA009696, AA088448,       270   TTTGTTAAAA   *   4.1   0.007   1.1   4.6   111244   ESTs   AA748351, AA769191,       271   AAGATAATGC   *   4.1   0.007   1.1   4.6   102898   ESTs, Weakly similar to C11D2.4 ( C. elegans )   AA806449, AA115687,       272   AAGATAATGC   *   4.1   0.007   1.1   4.6   251978   EST   C14037       273   TTTGTTAAAA   *   4.1   0.007   1.1   4.6   207118   EST   AJ806514       274   AGGAAAGCTG       4.0   0.000   6.3   25.0   76437   DKFZP5668023 protein   AA523344, AA551986,       275   CAAGCATCCC       3.5   0.000   5.8   20.4   153423   ESTs   AW275649, AW276934,       276   GAAATACAGT   *   −1.8   0.006   18.6   10.2   67201   ESTs   AA122047, AA404659,       277   TTCTGTGAAT   *   −3.7   0.002   8.5   2.3   77870   ESTs   AA022926, AA121431,       278   GAAATAATGG   *   −4.0   0.001   9.2   2.3   178053   ESTs   AA412270, AJ208372,       279   GAAATAATGG   *   −4.0   0.001   9.2   2.3   209037   ESTs   AJ143898, AJ808260       280   TATGACTTAA   *   −5.3   0.006   4.9   0.9   203352   ESTs   W52993       281   GTAAGATTAG   *   −5.8   0.000   8.1   1.4   250705   ESTs   AA953513, AJI28280,       282   GCCATATTAT       −5.8   0.009   2.7   0.0   19280   KIAA0544 protein   R70600, AJ081100,       283   AATTTTCATT   *   −6.3   0.008   2.9   0.0   77695   KIAA0008 gene product   AJ889277       284   AATTTTCATT   *   −6.3   0.006   2.9   0.0   35092   ESTs   AA343561, AA449815,       285   TTCCTCCTTT   *   −7.7   0.002   3.6   0.0   226144   ESTs   AJ215617, AJ982565,       286   GCTTGTCTTT       −7.7   0.002   3.6   0.0   224620   ESTs   AJ580377, AJ953171       287   ACAGTGTTAA       −7.7   0.002   3.6   0.0   186342   ESTs   AA167571, AA653213,       288   TTCCTCCTTT   *   −7.7   0.002   3.6   0.0   115581   EST, Highly similar to KIAA0826 protein ( H. sapiens )   AA463908       289   TTTTGTTTTG   *   −9.7   0.003   4.5   0.5   74867   ESTs   AA120854, AA489661,       290   ACAGATTTGA       −10.1   0.000   4.7   0.0   41271   ESTs   AA253217, AA599448,       291   TTCCCCCTTC       −10.6   0.000   4.9   0.0   163928   ESTs   AA577100, AJ819034       292   AAAGTCATTG   *   −11.1   0.001   5.1   0.5   21145   Human BAC clone RG083M05 from 7q21-7q22   AJ056386, AJ161119           SECTION 8.                           UNIDENTIFIED TRANSCRIPTS       293   CCGCCGAAGT       24.9   0.000   0.0   5.6       294   ACCTTTTCAA       16.8   0.000   0.0   3.7       295   GCCCCTCCGG       16.6   0.001   0.2   3.7       296   GCTTTCTCAC       10.4   0.000   0.9   9.3       297   CGCCGCGGCT       10.4   0.004   0.0   2.3       298   GTGACCACGG       9.3   0.001   0.4   4.2       299   GTTAACAGTC       8.3   0.010   0.0   1.9       300   GCCGTTCTTA       8.3   0.010   0.0   1.9       301   AGGCTACCGG       7.3   0.007   0.4   3.2       302   ACTTTTTCAC       5.4   0.000   1.8   9.7       303   TCCCCGTCAT       −4.5   0.003   6.3   1.4       304   AGGAATGTTA       −5.1   0.008   4.7   0.9       305   TCCCTTATTA       −5.3   0.008   4.9   0.9       306   TCTTGATATT       −5.8   0.009   2.7   0.0       307   AAGGCAATTT       −6.8   0.001   8.3   0.8       308   TTCGGTTGGT       −7.2   0.000   10.1   1.4       309   TCCCCGGTAC       −7.5   0.000   13.9   1.9       310   GCTGACGTCA       −8.2   0.001   3.8   0.0       311   TCCCCCGTAC       −8.7   0.001   4.0   0.0       312   ACGTTCTCTT       −9.2   0.001   4.3   0.0       313   TAACTTTTGG       −9.2   0.001   4.3   0.0       314   AAATGCTTGG       −9.7   0.003   4.5   0.5       315   CTAAAAACCT       −10.1   0.000   4.7   0.0       316   GTGAGAGTTT       −12.1   0.000   5.6   0.5       317   GGTGGACACG       −13.0   0.000   6.0   0.0       318   TCCCCTATTA       −15.4   0.000   7.2   0.0       319   CTTTATTCCA       −18.3   0.000   17.0   0.9                  
 
         [0205]    [0205]                                                                                                               TABLE IA                           Downstream targets induced by N-myc ribosomal proteins            Tag sequence   SHEP-2   SHEP-21N   Fold induction   P value   Unigene Hs.   Gene                    GCCGAGGAAG   1   37   37.0   &lt;0.001   82148   ribosomal protein S12       GCTTTTAAGG   1   29   29.0   &lt;0.001   8102   ribosomal protein S20       CCCATCCGAA   1   23   23.0   &lt;0.001   91379   ribosomal protein L26       GGCCGCGTTC   0   23   &gt;23   &lt;0.001   5174   ribosomal protein S17       CCAGTGGCCC   0   21   &gt;21   &lt;0.001   180920   ribosomal protein S9       GTGTTGCACA   1   16   16.0   &lt;0.001   165590   ribosomal protein S13       GATGCTGCCA   1   16   16.0   &lt;0.001   99914   ribosomal protein L22       CCGTCCAAGG   2   31   15.5   &lt;0.001   80617   ribosomal protein S16       GGAGTGGACA   1   14   14.0   &lt;0.001   75458   ribosomal protein L18       GCCTGTATGA   2   27   13.5   &lt;0.001   180450   ribosomal protein S24       GTTCCCTGGC   2   26   13.0   &lt;0.001   177415   ribosomal protein Fau-S30       ATGGCTGGTA   6   72   12.0   &lt;0.001   182426   ribosomal protein S2       GTGTTAACCA   1   11   11.0   &lt;0.001   74267   ribosomal protein L10       CACAAACGGT   4   43   10.8   &lt;0.001   195453   ribosomal protein S27       CTCAACATCT   3   32   10.7   &lt;0.001   73742   ribosomal protein, large, P0       GTTCGTGCCA   2   18   9.0   &lt;0.001   179666   ribosomal protein L35a       GACGACACGA   4   30   7.5   &lt;0.001   153177   ribosomal protein S28       TCGTCTTTAT   3   21   7.0   &lt;0.001   75538   ribosomal protein S7       GGACCACTGA   5   34   6.8   &lt;0.001   119598   ribosomal protein L3       CCTCGGAAAA   4   24   6.0   &lt;0.001   2017   ribosomal protein L38       AATCCTGTGG   8   48   6.0   &lt;0.001   178551   ribosomal protein L8       ATCAAGGGTG   4   21   5.3   &lt;0.001   157850   ribosomal protein L9       GGGCTGGGGT   20   101   5.1   &lt;0.001   183698   ribosomal protein L29       AAGGAGATGG   5   25   5.0   &lt;0.001   184014   ribosomal protein L31/tag matches                               mitochondrial sequences       AAGGTGGAGG   11   55   5.0   &lt;0.001   163593   ribosomal protein L18a       TTACCATATC   10   49   4.9   &lt;0.001   177461   ribosomal protein L39       GTGAAGGCAG   6   27   4.5   &lt;0.001   77039   ribosomal protein S3A       GAACACATCC   4   18   4.5   0.002   75879   ribosomal protein L19       CGCCGCCGGC   10   40   4.0   &lt;0.001   182825   human ribosomal protein L35 mRNA       GCCGTGTCCG   5   20   4.0   0.002   119213   ribosomal protein S6       AGGAAAGCTG   13   52   4.0   &lt;0.001   76437   ESTs, highly similar to 60S rpL36                               ( Rattus norvegicus )       CCCCAGCCAG   7   27   3.9   &lt;0.001   75459   ribosomal protein S3       GCAGCCATCC   13   48   3.7   &lt;0.001   4437   ribosomal protein L28       GGCAAGAAGA   7   25   3.6   &lt;0.001   111611   ribosomal protein L27       CCCGTCCGGA   19   65   3.4   &lt;0.001   180842   ribosomal protein L13       CGCTGGTTCC   15   51   3.4   &lt;0.001   179943   ribosomal protein L11       TAAGGAGCTG   9   30   3.3   &lt;0.001   77904   ribosomal protein S26       CCTTCGAGAT   8   26   3.3   0.001   76194   ribosomal protein S5       GGATTTGGCC   33   103   3.1   &lt;0.001   119500   ribosomal protein, large, P2       AGGCTACGGA   20   63   3.2   &lt;0.001   119122   60S ribosomal protein L13A       CTGCTATACG   7   22   3.1   &lt;0.004   180946   ribosomal protein L5       TGTGCTAAAT   12   35   2.9   &lt;0.001   179779   ribosomal protein L37       GAGGGAGTTT   34   97   2.9   &lt;0.001   76064   ribosomal protein L27a       AAGAAGATAG   8   22   2.8   0.007   184776   ribosomal protein L23a       ACATCATCGA   17   46   2.7   &lt;0.001   182979   ribosomal protein L12       CTGTTGGTGA   12   31   2.6   0.003   3463   ribosomal protein S23       AAGACAGTGG   26   63   2.4   &lt;0.001   184109   ribosomal protein L37a       TTGGTCCTCT   46   108   2.3   &lt;0.001   108124   ribosomal protein L41       CTCCTCACCT   12   28   2.3   0.008   119122   60S ribosomal protein L13A       AATAGGTCCA   22   50   2.3   &lt;0.001   113029   ribosomal protein S25       ACTCCAAAAA   23   46   2.0   0.004   133230   ribosomal protein S15       CTGGGTTAAT   47   87   1.9   &lt;0.001   126701   ribosomal protein S19       TCAGATCTTT   38   74   1.9   &lt;0.001   75344   ribosomal protein S4, X-linked       AGCTCTCCCT   38   56   1.9   0.003   82202   ribosomal protein L17       TAATAAAGGT   45   78   1.7   0.002   118690   ribosomal protein S8       TTCAATAAAA   56   89   1.6   0.004   177592   ribosomal protein, large, P1            Additional tags with P values &gt; 0.01 and ≦0.05            AAGGTCGAGC   1   8   8.0   0.022   184582   ribosomal protein L24       CTCGAGGAGG   0   6   &gt;6   0.016   3254   ribosomal protein L23-like       GCTCCGAGCG   0   5   &gt;5   0.028   80617   ribosomal protein S16       TACAAGAGGA   5   16   3.2   0.014   174131   ribosomal protein L6       CCATTGCACT   7   17   2.4   0.032   53798   ESTs, highly similar to 60S RP L18A       CGCCGGAACA   12   27   2.3   0.012   286   ribosomal protein L4       ATTATTTTTC   8   18   2.3   0.037   153   ribosomal protein L7       CAATAAATGT   34   53   1.6   0.027   179779   ribosomal protein L37       CCAGAACAGA   40   60   1.5   0.030   111222   ribosomal protein L30       GCATAATAGG   38   55   1.4   0.048   184108   ribosomal protein L21                    
         [0206]    [0206]                                                                                                                 Unigene       Accession       No.   Tag_Sequence   SHEP-2   SHEP-21N   P value   cluster   Unigene description   code                                1   CGACGAGGAG   1.8   7.0   0.0087   9999   epithelial membrane protein 3           2   TTTAAAAAAA*   21.7   7.0   0.0003   97437   centriole associated protein       3   GAATAAATGT   7.2   1.2   0.0053   8762   FK506-binding protein 9 (63 kD)   AI088246       4   TAAAATAAAA*   5.0   0.0   0.0027   87100   ESTs       5   TCTTCTGCCA   9.5   1.7   0.0021   86392   ESTs       6   TGCTTTGGGA   1.4   5.8   0.0100   84344   ESTs, Highly similar to CGI-135 protein [ H. sapiens ]   AA788733       7   GGGCGCTGTG   0.9   6.4   0.0020   8372   ubiquinol-cytochrome c reductase (6.4 kD) subunit       8   TTAGATAAGC*   4.5   12.2   0.0036   82916   chaperonin containing TCP1, subunit 6A (zeta 1)       9   AGCTCTCCCT   29.3   53.4   0.0000   82202   ribosomal protein L17   AA961432       10   CCCTGCCTTG   0.0   3.5   0.0052   82045   midkine (neurite growth-promoting factor 2)       11   GCACAAGAAG   9.6   19.2   0.0037   81634   ATP synthase, H+ transporting, mitochondrial                               F0 complex, subunit b, isoform 1       12   TTAAAGGCCG   0.5   5.2   0.0025   79086   ribosomal protein, mitochondrial, L3       13   AGAAAGATGT   9.5   20.3   0.0016   78225   annexin A1   AA846272       14   TTTAAAAAAA*   21.7   7.0   0.0003   77501   sarcoglycan, beta (43 kD dystrophin-associated glycoprotein)       15   GTAAAAAAAA*   44.7   20.9   0.0002   77495   UBX Domain-containing 1   AI492365       16   CTTGATTCCC   0.9   6.4   0.0020   77266   quiescin Q6       17   TGTGCTCGGG   2.3   7.6   0.0091   76847   KIAA0088 protein       18   CAGTCTCTCA   0.9   7.0   0.0010   76230   ribosomal protein S10       19   TACGTACTGC   0.0   3.5   0.0052   76086   ESTs, Highly similar to small zinc                               finger-like protein [ H. sapiens ]       20   GGCAAGCCCC   9.9   40.1   0.0000   76067   heat shock 27 kD protein 1   AI540836       21   CGGCTGAATT   0.9   5.8   0.0043   75888   phosphogluconate dehydrogenase       22   GGCTGGGGGC   19.4   38.3   0.0001   75721   profilin 1   AA903097       23   TGCTGGGTGG*   0.6   4.6   0.0056   754   folylpolyglutamate synthase       24   TCAGATCTTT   39.7   70.9   0.0000   75344   ribosomal protein S4, X-linked   AA954645       25   AAGAGTTTTG   0.5   5.8   0.0010   75313   aido-keto reductase family 1, member B1 (aldose reduclase)       26   ACAAATCCTT   1.8   7.0   0.0087   752   FK506-binding protein 1A (12 kD)       27   AATATGTGGG   5.4   12.8   0.0060   74649   cytochrome c oxidase subunit Vlc   AI025170       28   GGGTTTTTAT   5,0   11.6   0.0100   74497   nuclease sensitive element binding protein 1       29   TCTGCTTACA   2.7   8.1   0.0093   74267   ribosomal protein L15       30   TTTAAAAAAA*   21.7   7.0   0.0003   74088   early growth response 3       31   CAAACCATCC*   1.4   5.8   0.0100   65114   keratin 18       32   CAGACTTTTG*   5.9   12.8   0.0100   63348   DKFZP586M121 protein       33   TTGGGGTTTC   40.6   74.9   0.0000   62954   ferritin, heavy polypeptide 1   AA866040       34   AAGCCTTGCT   5.4   0.6   0.0098   6289   growth factor receptor-bound protein 2 [No, now   AI039721                               described as small stress protein-like protein HSP22       35   AAGAAACCTT   1.4   5.8   0.0100   5836   ESTs, Highly similar to CGI-138 protein [ H. sapiens ]       36   AAGGAAATGA   4.5   0.0   0.0043   57929   slit (Drosophila) homolog 3   AI741785       37   AACTAAAAAA*   68.6   91.8   0.0010   55921   glutamyl-prolyl-tRNA synthetase       38   ATAATTCTTT   73.1   102.8   0.0001   539   ribosomal protein S29       39   GTAAAAAAAA*   44.7   20.9   0.0002   460   Activating Transcription Factor 3   AA903193       40   TTTTAAAAAT*   7.7   1.7   0.0100   45033   lacrimal proline rich protein       41   CTCGAATAAA   4.5   0.0   0.0043   34871   KIAA0569 gene product   AI338485       42   AACTAAAAAA*   68.6   91.8   0.0010   3297   ribosomal protein S27a       43   GAGGCGATCA   0.0   3.5   0.0052   30783   ESTs, Weakly similar to eyelid [ D. melanogaster ]       44   GTGGCTGAAA   5.0   0.0   0.0027   29797   ribosomal protein L10   AI582446       45   GTTTCCCCAA*           0.0067   281434       46   GGTGAAGACA   8.6   1.2   0.0015   26951   Human mRNA for KIAA0375 gene, complete cds   AI080611       47   GCATTTAAAT*   16.7   27.3   0.0065   250876   eukaryotic translation elongation factor 1 beta 2       48   TTTTGTATTT   5.9   0.6   0.0055   250705   ESTs       49   CAGACTTTTG*   5.9   12.8   0.0100   250501   TNF? elastin microfibril interface located protein       50   GATCCCAACA   0.5   4.6   0.0056   25   ATP synthase, H+ transporting, mitochondrial                               F1 complex, beta polypeptide       51   CTGTTGATTG   16.3   26.7   0.0070   249495   heterogeneous nuclear ribonucleoprotein A1       52   CACGCAATGC*   0.5   5.8   0.0010   244   amino-terminal enhancer of split   AI015996       53   TGGTACACGT   0.9   5.8   0.0043   242463   keratin 8       54   TTTTAAAAAT*   7.7   1.7   0.0100   240013   catechol-O-methyltransferase       55   ATTCTCCAGT   48.8   72.6   0.0002   234518   ribosomal protein L23       56   CCCTTAGCTT   13.5   3.5   0.0011   233936   myosin, light polypeptide, regulatory, non-sarcomeric (20 kD)   AI033904       57   GTGGTGGGCG*   0.9   7.0   0.0010   233694   ESTs, Weakly similar to ZK1058.5 [ C. elegans ]       58   GCGGGGTACC   1.4   5.8   0.0100   227823   pM5 protein       59   GGAGAGTACA   0.0   3.5   0.0052   225939   sialyltransferase 9 (CMP-NeuAc:lactosylceramide                               alpha-2,3-sialyltransferase; GM3 synthase)       60   TAAAATAAAA*   5.0   0.0   0.0027   21254   TRAF Interacting protein       61   GTGGTGGGCG*   0.9   7.0   0.0010   209741   EST       62   GTGGTGGGCG*   0.9   7.0   0.0010   208985   ESTs       63   TCCAAATCGA   6.8   1.2   0.0080   2064   vimentin       64   TAAAATAAAA*   5.0   0.0   0.0027   204144   ESTs, Moderately similar to tumor necrosis factor-alpha-Induced                               protein B12 [ H. sapiens ]       65   TAAAATAAAA*   5.0   0.0   0.0027   202218   EST       66   TTCAATAAAA*   58.7   93.0   0.0000   2012   transcobalamin I (vitamin B12 binding protein, R binder family)   AI738761       67   TGCTGGGTGG*   0.5   4.6   0.0056   198273   NADH dehydrogenase (ubiquinone) 1 beta                               subcomplex, 8 (19 kD, ASHI)       68   TAAAATAAAA*   5.0   0.0   0.0027   190401   ESTs, Weakly similar to predicted                               using Genefinder [ C. elegans ]       69   AAGGTCGAGC   1.8   7.0   0.0087   184582   ribosomal protein L24       70   GCATAATAGG   31.6   54.0   0.0001   184108   ribosomal protein L21   AI224420       71   GTAAAAAAAA*   44.7   20.9   0.0002   183842   Ubiquitin B   AA988708       72   TAATATTTTT   11.7   2.9   0.0020   182485   actinin, alpha 4       73   GAAAAATGGT   48.3   87.7   0.0000   181357   laminin receptor 1 (67 kD, ribosomal protein SA)   AI025931       74   AGAACCTTAA   5.0   0.0   0.0027   181244   major histocompatibllity complex, class I, A   AI023950       75   CTCATAAGGA   49.2   70.9   0.0006   181165   eukaryotic translation elongation factor 1 alpha 1       76   TAATTTTGGA   9.0   17.4   0.0078   180152   ESTs       77   CAATAAATGT   37.0   57.5   0.0004   179779   ribosomal protein L37       78   TTCAATAAAA*   58.7   93.0   0.0000   177592   ribosomal protein, large, P1   AA961386       79   TTAAATAGCA   6.8   0.6   0.0021   172928   collagen, type I, alpha 1   AA992596       80   GGAGGAGAGC   5.0   0.0   0.0027   172928   collagen, type I, alpha 1       81   TGAAATTGTC   4.5   0.0   0.0043   172928   collagen, type I, alpha 1       82   AATGCAGGCA   1.4   6.4   0.0067   172673   S-adenosylhomocysteine hydrolase   AI051370       83   TTCCGGTTCC   9.0   1.7   0.0030   172609   nucleobindin 1   AI025019       84   CACGCAATGC*   0.5   5.8   0.0010   170683   EST   AI015996       85   TAGACTTATT   0.5   4.6   0.0056   170197   glutamic-oxaloacetic transaminase 2,                               mitochondrial (aspartate aminotransferase 2)       86   TTCACAGTGG   0.5   5.2   0.0025   169992   protein phosphatase 3 (formerly 2B), regulatory                               subunit B (19 kD), alpha isoform (calclneurin B, type I)       87   TGCACGTTTT   37.5   61.0   0.0001   169793   ribosomal protein L32   AA922605       88   GCAGCTCAGG   2.3   7.6   0.0091   167137   ESTs, Moderately similar to CATHEPSIN D                               PRECURSOR [ H. sapiens ]       89   GGTGAGACAC   2.7   8.7   0.0071   164280   solute carrier family 25 (mitochondrlal carrier; adenine                               nucleotide translocator), member 6       90   TTTAAAAAAA*   21.7   7.0   0.0003   155545   37 kDa leucine-rich repeat (LRR) protein       91   ATGTCATCAA   1.4   7.0   0.0030   152936   adaptor-related protein complex 2, mu 1 subunit       92   TAATAAAGGT   45.1   62.2   0.0029   151604   ribosomal protein S8   AI312878       93   TTAAAACAAA   4.1   0.0   0.0070   150508   ESTs   AI280093       94   TGGCCTAAAA   4.5   0.0   0.0043   1501   syndecan 2 (heparan sulfate proteoglycan 1,   AI005403                               cell surface-associated, fibroglycan)       95   GGTTAATTGA   4.1   0.0   0.0070   14376       AI590977       96   TTCAATAAAA*   58.7   93.0   0.0000   141269   ESTs   AA961386       97   ATGTGAAGAA   6.8   1.2   0.0080   13662     Homo sapiens  clone 25036 mRNA sequence   AI279223       98   TTTAAAAAAA*   21.7   7.0   0.0003   134533   ESTs       99   TTAGATAAGC*   4.5   12.2   0.0036   134350   ESTs       100   GTGACAGAAG   5.4   13.4   0.0034   129673   eukaryotic translation Initiation factor 4A, Isoform 1       101   CTGGGTTAAT   42.4   77.8   0.0000   126701   ribosomal protein S19   AA865047       102   CAAACCATCC*   1.4   5.8   0.0100   125170   ESTs       103   GGGACTGGGC*   0.5   5.2   0.0025   122256   ESTs       104   GCATTTAAAT*   16.7   27.3   0.0065   120979   ESTs       105   TAGGTTGTCT   55.1   71.5   0.0057   119252   tumor protein, translationally-controlled 1   AA808956       106   GACGTGTGGG   0.0   4.6   0.0009   119192   H2A histone family, member Z       107   GGCTTTACCC   9.0   20.9   0.0006   119140   eukaryotic translation initiation factor 5A       108   AACTAATACT   4.5   12.8   0.0022   118724   DR1-associated protein 1 (negative cofactor 2 alpha)   AI028098       109   TAAAATAAAA*   5.0   0.0   0.0027   118246   ESTs       110   GGGACTGGGC*   0.5   5.2   0.0025   117848   hemoglobin, epsilon 1       111   TAAAAACAAA   5.4   0.6   0.0098   114599       AW029321,                                   W1923       112   GTTTCCCCAA*   1.4   6.4   0.0067   112423     Homo sapiens  mRNA; cDNA DKFZp586I1420                               (from clone DKFZp586I1420)       113   GCAAAAAAAA   67.3   31.4   0.0000   11221   ESTs, Weakly similar to fos395541_1 [ H. sapiens ]   AI057027       114   CCAGAACAGA   37.5   55.8   0.0011   111222   ribosomal protein L30       115   GTACGGAGAT   0.5   4.6   0.0056   109225   vascular cell adhesion molecule 1       116   GTTTCCCCAA*   1.4   6.4   0.0067   107573   sialyltransferase       117   GGCCCCTCAC   0.5   4.6   0.0056   106283   Insulin-like growth factor binding protein 6       118   TTTAAAAAAA*   21.7   7.0   0.0003   106204   ESTs, Moderately similar to antigen containing epitope                                   to monoclonal antibody MMS-85/12 [ M. musculus ]       119   CCTCCCCCGT   0.9   5.2   0.0092   10488   Breakpoint cluster region protein, uterine                               leiomyoma, 1; barrier to autointegration factor       120   AGCAGGGCTC   0.0   5.2   0.0004   100623   phospholipase C, beta 3, neighbor pseudogene       121   AATTGCAAGC   5.0   0.0   0.0027   —       U50523       122   TTTAACGGCC   43.8   12.8   0.0000   —       AA196553       123   CATTGCCTTC   5.9   0.6   0.0055   —       124   GCTTGCTGCC   4.5   0.0   0.0043   —       125   AAAACATTCT   67.7   32.5   0.0000   —       AI538076       126   GCAGACATTG   0.9   5.8   0.0043   —       127   ACCCTTGGCC   12.2   26.7   0.0003   —       128   AGTAGGTGGC   8.1   1.7   0.0068   —   U5 snRNP-specific protein (220 kD),                               ortholog of S. cerevisiae Prp8p       129   GCAAGCCAAC   16.7   33.1   0.0002   —   actinin, alpha 1   Al669642       130   TTAGCTTGTT   4.1   0.0   0.0070   —       131   GTAATAACTT   4.1   0.0   0.0070   —       132   CGCCGTCGGC   0.0   3.5   0.0052   —       133   ACTCTTTCAA   0.5   4.6   0.0056   —       134   TGCTACGAAA   5.9   0.6   0.0055   —       135   CCCCGGTACA   7.2   1.2   0.0053   —       136   TTATAAAAGA   10.8   3.5   0.0098   —                    
         [0207]    [0207]                                                                                                   TABLE 1                           MYCN regulated genes (grouped by functional category)                        Ratio                                           ON:   P       SHEP-   Unigene               No.   Tag Sequence   nd   OFF   value   SHEP-2   21N   Cluster   Unigene Description   Accession code                                                    RIBOSOMAL PROTEINS           1   GGCCGCGTTC       47.7   0.000   0.00   10.7   5174   ribosomal protein S17   AA876041,           (SEQ ID NO: 1)                               AI564812,       2   CCAGTGGCCC       43.5   0.000   00.0   9.7   180920   ribosomal protein S9   AI064904, U14971           (SEQ ID NO: 2)       3   GCCGAGGAAG       38.3   0.000   0.4   17.2   82148   ribosomal protein S12   AA483128,           (SEQ ID NO: 3)                               AA524764,       4   GGAGTGGACA       29.0   0.000   0.2   6.5   75458   ribosomal protein L18   L11566, AA513721,           (SEQ ID NO: 4)       5   GTTAACGTCC       26.9   0.000   0.2   6.0   178391   L-44-like ribosomal protein (L44L),  Homo     W05120, AA181201,           (SEQ ID NO: 5)                             sapiens  Bruton&#39;s tyrosine kinase (BTK) alpha-                                       D-galactosidase A (GLA)       6   GCTTTTAAGG       20.7   0.000   0.7   13.9   8102   ribosomal protein S20   AI741190,           (SEQ ID NO: 6)                               AA064902,       7   GTGTTGCACA       16.6   0.000   0.4   7.4   165590   ribosomal protein S13   AI350382,           (SEQ ID NO: 7)                               AI290903,       8   CCGTCCAAGG       16.6   0.000   0.9   14.8   80617   ribosomal protein S16   AI262556,           (SEQ ID NO: 8)                               AA628078,       9   CTCGAGGAGG       12.4   0.006   0.2   2.8   3254   ribosomal protein L23-like   U26596, Z49254,           (SEQ ID NO: 9)       10   TCTCTTTTTC   ·   12.4   0.006   0.2   2.8   1948   ribosomal protein S21   AW196629           (SEQ ID NO: 10)       11   GTTCGTGCCA       12.4   0.000   0.7   8.3   179666   ribosomal protein L35a   AW328435,           (SEQ ID NO: 11)                               AW328458,       12   GTGTTAACCA       11.4   0.000   0.4   5.1   74267   ribosomal protein L15   AW327407,           (SEQ ID NO: 12)                               AA669521,       13   CTCAACATCT       11.4   0.000   1.3   15.3   73742   ribosomal protein, large, P0   AA807754,           (SEQ ID NO: 13)                               AI174682,       14   ATGGCTGGTA       11.0   0.000   3.1   34.3   182426   ribosomal protein S2   X17206, AA704039,           (SEQ ID NO: 14)       15   AATCCTGTGG       9.9   0.000   2.2   22.3   178551   ribosomal protein L8   AW327732,           (SEQ ID NO: 15)                               AI200056,       16   GACGACACGA       9.2   0.000   1.6   14.4   153177   ribosomal protein S28   AA229774,           (SEQ ID NO: 16)                               AA421061,       17   TCTTCTCACA   ·   8.3   0.010   0.0   1.9   126400   ESTs, Highly similar to 60S RIBOSOMAL   AA075869           (SEQ ID NO: 17)                           PROTEIN L39 ( H. sapiens )       18   GCCTGTATGA       8.0   0.000   1.6   12.5   180450   ribosomal protein S24   AW410149, D51704,           (SEQ ID NO: 18)       19   TGGTGTTGAG       7.7   0.000   2.2   17.2   75362   ribosomal protein S18   AA179543,           (SEQ ID NO: 19)                               AW409851,       20   CCTCGGAAAA       7.4   0.000   1.6   11.6   2017   ribosomal protein L38   AA659304,           (SEQ ID NO: 20)                               AA747113,       21   CCCATCCGAA       7.1   0.000   1.6   11.1   91379   ribosomal protein L26   AA084377,           (SEQ ID NO: 21)                               AA111974,       22   GATGCTGCCA       6.6   0.000   1.1   7.4   99914   ribosomal protein L22   AA420829,           (SEQ ID NO: 22)                               AA603500,       23   ATCAAGGGTG       6.0   0.000   1.8   10.7   157850   ribosomal protein L9   D14531, U09953,           (SEQ ID NO: 23)       24   CGCCGCCGGC       5.9   0.000   3.1   18.6   182825   ribosomal protein L35   AA457581,           (SEQ ID NO: 24)                               AA479946,       25   GGACCACTGA       5.9   0.000   2.7   15.8   119598   ribosomal protein L3   AA121930,           (SEQ ID NO: 25)                               AW022183,       26   CAGCTCACTG       5.7   0.002   0.9   5.1   158675   ribosomal protein L14   AA857488,           (SEQ ID NO: 26)                               AA186408,       27   GGGCTGGGGT       5.7   0.000   8.3   46.8   183698   ribosomal protein L29   U10248, U49083,           (SEQ ID NO: 27)       28   AAGGTGGAGG       5.3   0.000   4.9   26.0   163593   ribosomal protein L18a   AI719134,           (SEQ ID NO: 28)                               AA047273,       29   CACAAACGGT       5.2   0.000   4.0   20.9   195453   ribosomal protein S27 (metallopanstimulin 1)   AA525023,           (SEQ ID NO: 29)                               AA555149,       30   CCCCAGCCAG       5.1   0.000   2.5   12.5   252259   ribosomal protein S3   AA706649,           (SEQ ID NO: 30)                               AI792490,       31   TCGTCTTTAT       4.8   0.000   2.0   9.7   75538   ribosomal protein S7   M77233, AA513485,           (SEQ ID NO: 31)       32   GTTCCCTGGC       4.7   0.000   2.7   12.5   177415   ribosomal protein S30; Finkel-Biskis-Reilly   AA025263,           (SEQ ID NO: 32)                           murine sarcoma virus (FBR-MuSV)   AA055838,                                       ubiquitously expressed       33   GAACACATCC       4.7   0.000   1.8   8.3   75879   ribosomal protein L19   AI219423,           (SEQ ID NO: 33)                               AA075993,       34   CTGCTATACG       4.6   0.000   2.2   10.2   180946   ribosomal protein L5   W95798, AA491764,           (SEQ ID NO: 34)       35   CCCATCGTCC   ·   4.3   0.000   21.5   91.4   151604   ribosomal protein S8   AI357743,           (SEQ ID NO: 35)                               AW051118,       36   GCAGCCATCC       4.1   0.000   5.4   22.3   4437   ribosomal protein L28   AA225830,           (SEQ ID NO: 36)                               AA480489,       37   AAGGAGATGG       4.0   0.000   3.1   12.5   184014   ribosomal protein L31   AA340384,           (SEQ ID NO: 37)                               AA024502,       38   CCCGTCCGGA       4.0   0.000   7.6   30.1   180842   ribosomal protein L13   AI808685,           (SEQ ID NO: 38)                               AI992115,       39   CTGTTGGTGA       3.9   0.000   4.0   15.8   3463   ribosomal protein S23   AW020385,           (SEQ ID NO: 39)                               AW022474,       40   AGGGCTTCCA       3.8   0.000   5.1   19.5   29797   ribosomal protein L10   AA244126,           (SEQ ID NO: 40)                               AA508386,       41   TAAGGAGCTG       3.8   0.000   3.8   14.4   77904   ribosomal protein S26   AW022428, X69654,           (SEQ ID NO: 41)       42   GTGAAGGCAG       3.7   0.000   3.4   12.5   77039   ribosomal protein S3A   AA070817,           (SEQ ID NO: 42)                               AA074191,       43   CGCCGGAACA       3.4   0.000   3.8   13.0   286   ribosomal protein L4   AL119264,           (SEQ ID NO: 43)                               AW021149,       44   AGGCTACGGA       3.4   0.000   8.7   29.7   119122   ribosomal protein L13a   AA190354,           (SEQ ID NO: 44)                               AW328422,       45   CCTTCGAGAT       3.3   0.000   4.0   13.5   76194   ribosomal protein S5   AI971757,           (SEQ ID NO: 45)                               AA057826,       46   AAGACAGTGG       3.3   0.000   9.2   30.1   184109   ribosomal protein L37a   AA353060,           (SEQ ID NO: 46)                               AW020311,       47   TTACCATATC       3.3   0.000   6.9   22.7   177461   ribosomal protein L39   AW023657, T40220,           (SEQ ID NO: 47)       48   TGTGCTAAAT       3.2   0.000   5.1   16.7   250695   ribosomal protein L34   AW020881, N85940,           (SEQ ID NO: 48)       49   GCCGTGTCCG       3.2   0.001   2.9   9.3   241507   ribosomal protein S6   AA148286,           (SEQ ID NO: 49)                               AA167421,       50   GGCAAGAAGA       3.0   0.000   3.8   11.6   111611   ribosomal protein L27   AA531226,           (SEQ ID NO: 50)                               AA885969,       51   ACATCATCGA       3.0   0.000   7.4   22.3   182979   ribosomal protein L12   L06505, AA484253,           (SEQ ID NO: 51)       52   GGATTTGGCC       2.9   0.000   16.8   48.2   251247   ribosomal protein, large P2   AA037465,           (SEQ ID NO: 52)                               AA064832,       53   CGCTGGTTCC       2.8   0.000   8.5   24.1   179943   ribosomal protein L11   AA226392,           (SEQ ID NO: 53)                               AA230322,       54   TACAAGAGGA       2.8   0.006   2.7   7.4   174131   ribosomal protein L6   AI042168, D17554           (SEQ ID NO: 54)       55   TTGGTCCTCT       2.7   0.000   18.4   50.1   108124   ribosomal protein L41   Z12962, AA045319,           (SEQ ID NO: 55)       56   CTCCTCACCT       2.6   0.001   4.9   13.0   119122   ribosomal protein L13a   AW242158,           (SEQ ID NO: 56)                               AW245640,       57   AATAGGTCCA       2.5   0.000   9.2   23.2   113029   ribosomal protein S25   AA228780,           (SEQ ID NO: 57)                               AA229897,       58   GAGGGAGTTT       2.5   0.000   18.6   46.8   76064   ribosomal protein L27a   AA228189,           (SEQ ID NO: 58)                               AA229949,       59   AAGAAGATAG       2.5   0.002   4.3   10.7   184776   ribosomal protein L23a   AA040728,           (SEQ ID NO: 59)                               AA088884,       60   ATTATTTTTC       2.5   0.006   3.6   8.8   153   ribosomal protein L7   AA138446,           (SEQ ID NO: 60)                               AW020191,       61   ACTCCAAAAA       2.2   0.000   10.3   22.7   133230   ribosomal protein S15   AA079663,           (SEQ ID NO: 61)                               AA151459,           SECTION 2                           PROTEIN SYNTHESIS       62   CTGGCGAGCG       18.6   0.000   0.2   4.2   174070   ubiquitin carrier protein   AA211097,           (SEQ ID NO: 62)                               AA283711,       63   GAGCGGGATG       16.6   0.001   0.2   3.7   77060   proteasome (prosome, macropain) subunit   D29012, X61971,           (SEQ ID NO: 63)                           beta type, 6       64   GCATAGGCTG       12.4   0.000   0.4   5.6   12084   Tu translation elongation factor,   AL037768, L38995,           (SEQ ID NO: 64)                           mitochondrial       65   GGCTCCCACT       11.7   0.000   0.7   7.9   74335   heat shock 90 kD protein 1, beta   AW023752,           (SEQ ID NO: 65)                               AA034511,       66   GCCCAGCTGG       11.4   0.000   0.4   5.1   223241   eukaryotic translation elongation factor 1 delta   Z21507, AA489523,           (SEQ ID NO: 66)                           (guanine nucleotide exchange protein)       67   TGAAATAAAC   ·   10.4   0.004   0.0   2.3   173205   nucleophosmin (nucleolar phosphoprotein   AI184619           (SEQ ID NO: 67)                           B23, numatrin)       68   TACCAGTGTA       10.4   0.004   0.0   2.3   79037   heat shock 60 kD protein 1 (chaperonin)   AW021205,           (SEQ ID NO: 68)                               AW103323,       69   TGTGTTGAGA       9.4   0.000   5.6   52.4   181165   eukaryotic translation elongation factor 1   AA630271,           (SEQ ID NO: 69)                           alpha 1   AA668532,       70   TGGGCAAAGC       9.0   0.000   2.0   18.1   2188   eukaryotic translation elongation factor 1   AA038923,           (SEQ ID NO: 70)                           gamma   AA190762,       71   ACATCCTCAC       8.3   0.010   0.0   1.9   18700   proteasome (prosome, macropain) 26S   AA024838,           (SEQ ID NO: 71)                           subunit, non-ATPase, 13   AA149127,       72   TAAAATTTGT   ·   8.3   0.010   0.0   1.9   93379   eukaryotic translation initiation factor 4B   AA054750,           (SEQ ID NO: 72)                               AA133563,       73   CAGTCTAAAA       8.3   0.003   0.4   3.7   76118   ubiquitin carboxyl-terminal esterase L1   X04741, AA029783,           (SEQ ID NO: 73)                           (ubiquitin thiolesterase)       74   GAAGGCATCC       8.3   0.010   0.0   1.9   250758   proteasome (prosome, macropain) 28S   F32284, AA130329,           (SEQ ID NO: 74)                           subunit, ATPase, 3       75   TGGCTAGTGT       6.9   0.001   0.7   4.6   118865   proteasome (prosome, macropain) subunit,   AA804284,           (SEQ ID NO: 75)                           beta type, 7   AA829376,       76   CAGATCTTTG       5.8   0.000   1.1   6.5   119502   ubiquitin A-52 residue ribosomal protein   AF075321,           (SEQ ID NO: 76)                           fusion product 1   AI110823,       77   TCACAAGCAA       4.4   0.001   1.6   7.0   146763   nascent-polypeptide-associated complex alpha   AF054187, X80909,           (SEQ ID NO: 77)                           polypeptide       78   AACTCTTGAA       3.6   0.006   1.3   5.1   58189   eukaryotic translation initiation factor 3,   U54559, AA024720,           (SEQ ID NO: 78)                           subunit 3 (gamma, 40 kD)       79   AGCACCTCCA       3.5   0.000   9.0   31.5   75309   eukaryotic translation elongation factor 2   AA229607,           (SEQ ID NO: 79)                               AA533837,       80   AGCCCTACAA   ·   3.4   0.000   15.4   52.9   180532   heat shock 90 kD protein 1, alpha   AW088888,           (SEQ ID NO: 80)                               AW128905,       81   CGCCGCGGTG       2.9   0.004   2.7   7.9   4835   eukaryotic translation initiation factor 3,   AA573953,           (SEQ ID NO: 81)                           subunit 8 (110 kD)   AA778265,       82   TTCATACACC   ·   2.6   0.000   31.3   82.8   180532   heat shock 90 kD protein 1, alpha   AW080984           (SEQ ID NO: 82)       83   TGAAATAAAA       2.5   0.000   10.1   25.5   173205   nucleophosmin (nucleolar phosphoprotein   AI926288,           (SEQ ID NO: 83)                           B23, numatrin)   AW166350,       84   ATCAGTGGCT       2.5   0.009   3.1   7.9   89545   proteasome (prosome, macropain) subunit,   R25997, R68878,           (SEQ ID NO: 84)                           beta type, 4       85   CCCTGATTTT       −7.1   0.000   9.8   1.4   183684   eukaryotic translation initiation factor 4   U73824, U76111,           (SEQ ID NO: 85)                           gamma, 2       86   AAGAGGTTTG       −9.2   0.001   4.3   0.0   74368   transmembrane protein (63 kD), endoplasmic   X69910, AI131495,           (SEQ ID NO: 86)                           reticulum/Golgi intermediate compartment       87   GTTTTTGCTT       2.4   0.075   1.6   3.7   79110   Nucleolin   AA133588,           (SEQ ID NO: 87)                               AA135423, A       88   TACAAAACCA       2.1   0.923   0.9   1.9   79110   Nucleolin   AA088423,           (SEQ ID NO: 88)                               AA284953, A           SECTION 3.                           GENES INVOLVED IN METASTASIS       89   AATAGAAATT       14.5   0.000   0.0   3.2   313   secreted phosphoprotein 1 (osteopontin, bone   AW021049,           (SEQ ID NO: 89)                           sialoprotein 1, early T-lymphocyte activation   AA021512,                                       1)       90   ATGCTCCCTG       14.5   0.000   0.0   3.2   79339   lectin, galactoside-binding, soluble, 3 binding   L13210, X79089           (SEQ ID NO: 90)                           protein (galectin 6 binding protein)       91   ACAGGGTGAC       14.5   0.000   0.0   3.2   174050   endothelial differentiation-related factor 1   AA975055,           (SEQ ID NO: 91)                               AA992919,       92   AACGCGGCCA       12.8   0.000   1.1   14.4   73798   macrophage migration inhibitory factor   AA523321,           (SEQ ID NO: 92)                           (glycosylation-inhibiting factor)   AA927284       93   AAGAAAGGAG       11.4   0.000   0.9   10.2   202097   procollagen C-endopeptidase enhancer   L33799           (SEQ ID NO: 93)       94   GTAAGTCTCA       8.3   0.010   0.0   1.9   211584   neurofilament, light polypeptide (68 kD)   AW022557,           (SEQ ID NO: 94)                               AA330627,       95   GCCGATCCTC       8.3   0.010   0.0   1.9   24930   tubulin-specific chaperone a   AF038952           (SEQ ID NO: 95)       96   GGCTCCTGGC       8.3   0.010   0.0   1.9   5215   integrin beta 4 binding protein   AF022229,           (SEQ ID NO: 96)                               AF047433,       97   GCCGGGTGGG       7.6   0.001   0.7   5.1   74631   basigin   D45131, L10240,           (SEQ ID NO: 97)       98   GGGGAAATCG       5.9   0.000   3.8   22.3   76293   thymosin, beta 10   AA147288,           (SEQ ID NO: 98)                               AA155816,       99   GCCCCCAATA       −1.7   0.007   20.1   11.6   227751   lectin, galactoside-binding, soluble, 1   J04456, X14829,           (SEQ ID NO: 99)                           (galectin 1)       100   ACCAAAAACC       −1.8   0.003   21.3   11.6   172928   collagen, type I, alpha 1   AA454809,           (SEQ ID NO: 100)                               AA454820,       101   GTTGTGGTTA       −2.2   0.000   30.0   13.9   75415   beta-2-microglobulin   AB021288,           (SEQ ID NO: 101)                               AA897072,       102   AACTGCTTCA       −2.5   0.002   12.8   5.1   11538   actin related protein 2/3 complex, subunit fB   AA031434,           (SEQ ID NO: 102)                           (41 kD)   AA045773,       103   TCTCTGATGC       −2.7   0.001   12.5   4.6   6441   tissue inhibitor of metalloproteinase 2   AL110197,           (SEQ ID NO: 103)                               AL134962,       104   TGTACCTGTA       −2.8   0.000   14.1   5.1   169476   tubulin, alpha, ubiquitous   AA018607,           (SEQ ID NO: 104)                               AA018627,       105   GCTTTATTTG       −2.9   0.000   15.9   5.6   180952   actin, beta   AA419273,           (SEQ ID NO: 105)                               AA528145,       106   TCCTGTAAAG       −3.1   0.007   7.2   2.3   74034   caveolin 1, caveolae protein, 22 kD   AA034380,           (SEQ ID NO: 106)                               AA044994,       107   TGCTAAAAAA       −4.7   0.000   17.5   3.7   146550   myosin, heavy polypeptide 9, non-muscle   AA041529,           (SEQ ID NO: 107)                               AA070528,       108   TGGAAATGAC       −4.9   0.000   42.8   8.8   172928   collagen, type I, alpha 1   AA853342,           (SEQ ID NO: 108)                               AA436411,       109   TGGAAATGCC       −5.0   0.001   6.9   1.4   172928   collagen, type I, alpha 1   AI190987,           (SEQ ID NO: 109)                               AI339782,       110   GTTTTTTTTA   ·   −5.5   0.004   5.1   0.9   179573   collagen, type I, alpha 2   AI825593           (SEQ ID NO: 110)       111   ACAGGCTACG       −6.0   0.002   5.6   0.9   75777   transgelin   AI188763,           (SEQ ID NO: 111)                               AI540294,       112   TAAAAATGTT       −6.3   0.000   17.5   2.8   82085   plasminogen activator inhibitor, type I   M14083, AA040151,           (SEQ ID NO: 112)       113   GTTTCTAATA       −6.3   0.006   2.9   0.0   239298   microtubule-associated protein 4   AA043400,           (SEQ ID NO: 113)                               AA086286,       114   TTAAAGATTT       −7.1   0.000   13.2   1.9   77899   tropomyosin 1 (alpha)   AA026364,           (SEQ ID NO: 114)                               AA036782,       115   GACCGCAGGA       −7.2   0.003   3.4   0.0   119129   collagen, type IV, alpha 1   X03883, AW020005,           (SEQ ID NO: 115)       116   TAATCCTCAA       −8.2   0.000   7.6   0.9   78409   collagen, type XVIII, alpha 1   AA009957,           (SEQ ID NO: 116)                               AA099281,       117   TGTAGAAAAA       −9.2   0.004   4.3   0.5   119076   tubulin, beta polypeptide   AI308800,           (SEQ ID NO: 117)                               AI623884,       118   TTAGTGTCGT       −10.6   0.002   4.9   0.5   111779   secreted protein, acidic, cysteine-rich   AW020585,           (SEQ ID NO: 118)                           (osteonectin)   AW022769,       119   GCCCCAATAA   ·   −11.1   0.000   5.1   0.0   227751   lectin, galactoside-binding, soluble, 1   AA095630           (SEQ ID NO: 119)                           (galectin I)       120   AAAGTCATTG   ·   −11.1   0.001   5.1   0.5   77899   tropomyosin 1 (alpha)   M19713           (SEQ ID NO: 120)       121   TGCAATATGC       −12.5   0.000   5.8   0.0   750   fibrillin 1 (Marfan syndrome)   L13923, X63556,           (SEQ ID NO: 121)       122   ATCTTGTTAC       −14.5   0.000   6.7   0.5   116162   fibronectin 1   AW020421,           (SEQ ID NO: 122)                               AW020447,       123   AAAAAGCTGC       −15.9   0.000   7.4   0.0   111779   secreted protein, acidic, cysteine-rich   AA987875,           (SEQ ID NO: 123)                           (osteonectin)   AI755199,       124   AAAATATTTT       −18.8   0.000   8.7   0.0   119000   actinin, alpha 1   X55187, AA024895,           (SEQ ID NO: 124)       125   ATGTGAAGAG       −19.9   0.000   268.2   13.5   111779   secreted protein, acidic, cysteine-rich   AA228362,           (SEQ ID NO: 125)                           (osteonectin)   AA852763,       126   TGGCCTAATA       −27.5   0.000   12.8   0.0   1501   syndecan 2 (heparin sulfate proteoglycan 1,   AA873519,           (SEQ ID NO: 126)                           cell surface-associated, fibroglycan)   AI279414,       127   TTTGCACCTT       −37.6   0.000   17.5   0.5   75511   connective tissue growth factor   AW021964, U14750,           (SEQ ID NO: 127)           SECTION 4.                           GLYCOLYSIS ENZYMES       128   TAGCTTCTTC       14.5   0.000   0.0   3.2   76392   aldehyde dehydrogenase 1, soluble   AA911018,           (SEQ ID NO: 128)                               AI150648,       129   ACCTTGTGCC       10.4   0.004   0.0   2.3   878   sorbitol dehydrogenase   AA570172,           (SEQ ID NO: 129)                               AA570189,       130   TCTGCTTGTC       10.4   0.004   0.0   2.3   76392   aldehyde dehydrogenase 1, soluble   H79748, H05271,           (SEQ ID NO: 130)       131   TGACTGAAGC       10.4   0.004   0.0   2.3   3343   3-phosphoglycerate dehydrogenase   AA742550,           (SEQ ID NO: 131)                               AA113268,       132   TGGCCCCACC       7.5   0.000   1.1   8.3   198281   pyruvate kinase, muscle   AA766601,           (SEQ ID NO: 132)                               AA768285,       133   GCGACCGTCA       7.3   0.000   0.9   6.5   183760   aldolase A, fructose-bisphosphate   AA169762,           (SEQ ID NO: 133)                               AA557193,       134   TACCATCAAT       4.7   0.000   5.8   27.4   195188   glyceraldehyde-3-phosphate dehydrogenase   AA226658,           (SEQ ID NO: 134)                               AA522734,       135   TGAGGGAATA       4.4   0.000   2.2   9.7   83848   triosphosphate isomerase 1   AA587096,           (SEQ ID NO: 135)                               AA587188,                                       MITOCHONDRIAL FUNCTION           SECTION 5.                           PROTEINS       136   GAATCGGTTA       22.8   0.000   0.2   5.1   80595   NADH dehydrogenase (ubiquinone) Fe-S   AF047434,           (SEQ ID NO: 136)                           (15 kD) (NDUFB4)   AA457600,       137   GGGGGTCACC       18.6   0.000   0.0   4.2   80986   ATP synthase, H+ transporting, mitochondrial   AA659764,           (SEQ ID NO: 137)                           F0 complex, subunit c (subunit 9), isoform 1   AA866065,       138   AAGGAGTTTG       14.5   0.000   0.0   3.2   661   NADH dehydrogenase (ubiquinone) 1 beta   AA493442,           (SEQ ID NO: 138)                           subcomplex, 7 (18 kD, B18)   AA832435,       139   AGGTCCTAGC       14.5   0.000   0.4   6.5   226795   glutathione S-transferase pi   F34719, U30897,           (SEQ ID NO: 139)       140   CTTAGAGCCC       12.4   0.006   0.2   2.8   211929   thioredoxin, mitochondrial   AI680239           (SEQ ID NO: 140)       141   TTCTGGCTGC       12.4   0.006   0.2   2.8   119251   ubiquinol-cytochrome c reductase core protein 1   F28971, AI005342,           (SEQ ID NO: 141)       142   GTGGTACAGG       7.3   0.007   0.4   3.2   31731   EST&#39;s, Highly similar to PUTATIVE   AA745952,           (SEQ ID NO: 142)                           PEROXISOMAL ANTIOXIDANT   AA829707,                                       ENZYME ( H. sapiens )       143   GTGACAACAC       5.2   0.003   0.9   4.6   149155   voltage-dependent anion channel 1   AA907238,           (SEQ ID NO: 143)                               AI075271,       144   GCCTGCTGGG       4.8   0.000   2.0   9.7   2706   glutathione peroxidase 4 phospholipid   X71973, AA743017,           (SEQ ID NO: 144)                           hydroperoxidase)       145   GGGGACTGAA       4.6   0.003   1.1   5.1   3709   low molecular mass ubiquinone-binding   AA010879,           (SEQ ID NO: 145)                            protein (9.5 kD)   AA025093,       146   CCCATCGTCC   ·   4.3   0.000   21.5   91.4   mito   cytochrome c oxidase II (Welle et al., 1999),   AA069405,           (SEQ ID NO: 146)                           Tag matches mitochondrial sequences   AA074137       147   TGATTTCACT   ·   4.1   0.000   4.0   18.7   mito   cytochrome c oxidase III (Welle et al., 1999),   AA757623           (SEQ ID NO: 147)                           Tag matches mitochondrial sequences       148   TGAAGGAGCC       4.1   0.007   1.1   4.6   89399   ATP synthase, H+ transporting, mitochondrial   F27013, D13119,           (SEQ ID NO: 148)                           F0 complex, subunit c (subunit 9), isoform 2       149   GTGACCTCCT       4.1   0.003   1.3   5.6   81097   cytochrome c oxidase subunit VIII   F28051, F28676,           (SEQ ID NO: 149)       150   AGCCCTACAA   ·   3.4   0.000   15.4   52.9   mito   NADH dehydrogenase 3 (Welle et al., 1999),   AA577697,           (SEQ ID NO: 150)                           Tag matches mitochondrial sequences   AI022799       151   TTCATACACC   ·   2.6   0.000   31.3   82.6   mito   NADH dehydrogenase 4/4L (Welle et al.,   AA971178           (SEQ ID NO: 151)                           1999), Tag matches mitochondrial sequences       152   CACCTAATTG   ·   2.3   0.000   34.2   79.3   mito   ATPase 6/8 (Welle et al., 1999), Tag matches   AA031407           (SEQ ID NO: 152)                           mitochondrial sequences       153   GAGAGCTCCC       −2.6   0.008   7.8   2.8   169919   electron-transfer-flavoprotein, alpha   AI364921           (SEQ ID NO: 153)                           polypeptide (glutaric aciduria II)       154   GTAAGATTAG   ·   −5.8   0.000   8.1   1.4   5417   oxygen regulated protein (150 kD)   AA828743           (SEQ ID NO: 154)       155   GCCCCAATAA   ·   −11.1   0.000   5.1   0.0   173554   ubiquinol-cytochrome c reductase core protein   AA425586           (SEQ ID NO: 155)                           II           SECTION 6.                           OTHER GENES       156   CCCCCTGGAT       21.8   0.000   0.4   9.7   N/A   calcyclin   AI832624,           (SEQ ID NO: 156)       157   GTGCGCTAGG       18.6   0.000   0.2   4.2   9408   ESTs, classified Into serine/threonine kinase,   AA420761,           (SEQ ID NO: 157)                           Highly similar to The KIAA0151gene product   AA492367,                                       is       158   GAGTGGGGGC       18.6   0.000   0.2   4.2   14089   ESTs, Weakly similar to LYSOSOMAL   AA362125,           (SEQ ID NO: 158)                           PRO-X CARBOXYPEPTIDASE   AA418395,                                       PRECURSOR ( H. sapiens )       159   TTTCCTTCCT   ·   16.6   0.001   0.2   3.7   104143   clathrin, light polypeptide (Lca)   AA574409,           (SEQ ID NO: 159)                               AA737504,       160   ATAAGATACA       16.6   0.000   0.0   3.7   199026   RAS p21 protein activator (GTPase activating   X69399           (SEQ ID NO: 160)                           protein) 3 (Ins(1,3,4,5)P4-binding protein       161   AACGCTGCCT       14.5   0.000   0.0   3.2   28914   adenine phosphoribosyltransferase   AA444001,           (SEQ ID NO: 161)                               AA535523       162   ATTTGTCCCA       12.4   0.000   0.4   5.6   139800   high-mobility group (nonhistone   AA071304,           (SEQ ID NO: 162)                           chromosomal) protein Isoforms I and Y   AA074087,       163   TCAGACGCAG       12.4   0.006   0.2   2.8   182371   prothymosin, alpha (gene sequence 28)   AW129309           (SEQ ID NO: 163)       164   TCTCTTTTTC   ·   12.4   0.006   0.2   2.8   119529   epididymal secretory protein (19.5 kD)   AA025798,           (SEQ ID NO: 164)                               AA039545,       165   TTTCAGGGGA   ·   12.4   0.006   0.2   2.8   2853   poly(rC)-binding protein 1   AI312897           (SEQ ID NO: 165)       166   CGGCCCAACG       12.4   0.001   0.0   2.8   20521   HMTI (hnRNP methytransferase, S,   AA031375,           (SEQ ID NO: 166)                           cerevisiae)-like 2   AA187773,       167   TTCTCCCGCT       12.4   0.001   0.0   2.8   118126   protective protein for beta-galactosidase   M22960, AI752680,           (SEQ ID NO: 167)                           (galactosialidosis)       168   GGGGGACGGC       12.4   0.001   0.0   2.8   21346   ESTs, Weakly similar to F42C5.7 gene   AA015864,           (SEQ ID NO: 168)                           product ( C. elegans )   AA026165,       169   GGCCCTGAGC       11.4   0.000   0.4   5.1   71618   polymerase (RNA) II (DNA directed)   AA570105,           (SEQ ID NO: 169)                           polypeptide L (7.6 kD), Human RNA   AA562657,                                       polymerase II subunit       170   TATGTGATTT       10.4   0.000   0.4   4.6   5216   ESTs, Highly similar to HSPC028 ( H. sapiens )   AA713577,           (SEQ ID NO: 170)                               AA748622,       171   GGCAGAGGAC       10.4   0.000   0.7   7.0   118638   non-metastatic cells I, protein (NM23A)   X17620, AA046312,           (SEQ ID NO: 171)                           expressed in       172   GCCAAGATGC       10.4   0.004   0.0   2.3   83135   p53-responsive gene 6   AA038471,           (SEQ ID NO: 172)                               AA149617,       173   CCCACACTAC       10.4   0.004   0.0   2.3   242024   guanine nucleotide binding protein (G   M16538, AA548194,           (SEQ ID NO: 173)                           protein), beta polypeptide 2       174   CCGTCATCCT       10.4   0.004   0.0   2.3   153591   Not56 ( D. melanogaster )-like protein   AI914552,           (SEQ ID NO: 174)                               AA412507,       175   TGAAATAAAC   ·   10.4   0.004   0.0   2.3   155212   methylmalonyl Coenzyme A mutase   AI569812,           (SEQ ID NO: 175)                               AI628986,       176   TGAAATAAAC   ·   10.4   0.004   0.0   2.3   238380   Human endogenous retroviral protease nRNA,   AA527289           (SEQ ID NO: 176)                           complete cds       177   GACCCTGCCC       10.4   0.004   0.0   2.3   173464   FK506-binding protein 8 (38 kD)   L37033, AA587607,           (SEQ ID NO: 177)       178   CAGCAGAAGC       9.8   0.000   0.9   8.8   256313   pinin, desmosome associated protein   N76807           (SEQ ID NO: 178)       179   CTCATAGCAG   ·   9.3   0.001   0.4   4.2   103636   chromosome 1 open reading frame 9   AI312752,           (SEQ ID NO: 179)                               AI312755,       180   CTCATAGCAG   ·   9.3   0.001   0.4   4.2   119252   tumor protein, translationally-controlled 1   N92214, AA045631,           (SEQ ID NO: 180)       181   CTGGGCCTGG       8.3   0.010   0.0   1.9   74573   similar to vaccinia virus HindIII K4L ORF   N99342, D45708,           (SEQ ID NO: 181)       182   GGGGTAAGAA       8.3   0.010   0.0   1.9   80423   prostatic binding protein   AA613924,           (SEQ ID NO: 182)                               AA825254,       183   GGGCTGGGCC       8.3   0.010   0.0   1.9   100071   6-phosphogluconolactonase   AI217069,           (SEQ ID NO: 183)                               AI279087,       184   TTTTTTGTAA       8.3   0.010   0.0   1.9   97858   SH3-domain binding protein 1   AA748769           (SEQ ID NO: 184)       185   GCAGTGGCCT       8.3   0.010   0.0   1.9   184276   solute carrier family 9 (sodium/hydrogen   AA425299,           (SEQ ID NO: 185)                           exchanger), Isoform 3 regulatory factor 1   AA593621,       186   CCCCCAATGC       8.3   0.010   0.0   1.9   115232   Spliceosome protein SAP-62   AI280056,           (SEQ ID NO: 186)                               AI348200,       187   CTGCTGTGAT   ·   8.3   0.010   0.0   1.9   1063   small nuclear ribonucleoprotein polypeptide C   AA089406,           (SEQ ID NO: 187)                               AA099919,       188   CAGTTGGTTG       8.3   0.010   0.0   1.9   155218   E1B-55 kDa-associated protein 5   AA130531,           (SEQ ID NO: 188)                               AA155800,       189   ATCCATAGTG       8.3   0.010   0.0   1.9   66772   TATA box binding protein (TBP)-associated   AA662359,           (SEQ ID NO: 189)                           factor, RNA polymerase II, N, 68 kD (RNA -   AA857343,                                       binding       190   CTGGATGCCG       8.3   0.010   0.0   1.9   106061   RD RNA-binding protein   AA569818,           (SEQ ID NO: 190)                               AA988602,       191   CTGACCCCCT       8.3   0.010   0.0   1.9   26492   beta-1,3-glucoronyltransferase 3   AB009598,           (SEQ ID NO: 191)                           (glucuronosyltransferase I)   AJ005865,       192   CCTGTACCCC   ·   8.3   0.010   0.0   1.9   32317   Sox-like transcriptional factor   AA045957,           (SEQ ID NO: 192)                               AA196459,       193   TAAAATTTGT   ·   8.3   0.010   0.0   1.9   32317   Sox-like transcriptional factor   AA919117           (SEQ ID NO: 193)       194   TGGCCTGCCC       8.3   0.010   0.0   1.9   181002   MLL septin-like fusion   AA761307,           (SEQ ID NO: 194)                               AA831791,       195   TGGCCTCCCC       8.3   0.010   0.0   1.9   159161   Rhp GDP dissociation Inhibitor (GDI) alpha   X69550           (SEQ ID NO: 195)       196   TGCAGCGCCT       8.3   0.010   0.0   1.9   77573   uridine phosphorylase   X90858, AI018589,           (SEQ ID NO: 196)       197   TGAGGGGTGA       8.3   0.010   0.0   1.9   252979   G protein pathway suppressor 1   AA521025,           (SEQ ID NO: 197)                               AA569807,       198   TGAGGCCAGG   ·   8.3   0.010   0.0   1.9   79162   structure specific recognition protein 1   AW328290, M85737,           (SEQ ID NO: 198)       199   GAGAGAAGAG       8.3   0.010   0.0   1.9   13476   UDP-GalbetaGlcNAc beta 1,4-   AA721091,           (SEQ ID NO: 199)                           galactosyltransferase, polypeptide 3   AA743639,       200   TCTTCTCACA   ·   8.3   0.010   0.0   1.9   656   cell division cycle 25C   AA206499,           (SEQ ID NO: 200)                               AA534482,       201   GCCGCTACTT       8.3   0.010   0.0   1.9   32989   calcitonin receptor-like receptor activity   AI951585,           (SEQ ID NO: 201)                           modifying protein 1   AJ001014,       202   CCCTCCTCCG       8.3   0.010   0.0   1.9   81131   guanidinoacetate N-methyltransferase   D59710, AI123221,           (SEQ ID NO: 202)       203   TATGACCACA   ·   8.3   0.010   0.0   1.9   6650   vacuolar protein sorting 45B (yeast homolog)   AA765898,           (SEQ ID NO: 203)                               AA769317,       204   TACATTCACC       8.3   0.010   0.0   1.9   82043   D123 gene product   D14876, U27112,           (SEQ ID NO: 204)       205   AAGCGGGACC       8.3   0.010   0.0   1.9   153436   N-acetyltransferase, homolog of  S. cerevisiae     X77588, AA158247,           (SEQ ID NO: 205)                           ARDI       206   GATCAATGGA   ·   8.3   0.010   0.0   1.9   3090   EphB1   AA449788,           (SEQ ID NO: 206)                               AA640161,       207   GATCAATGGA   ·   8.3   0.010   0.0   1.9   251788   glucosamine-6-phosphate deaminase   AA031910,           (SEQ ID NO: 207)                               AA151768,       208   GCCGCCATCT       8.3   0.010   0.0   1.9   89643   transkelolase (Wernicke-Korsakoff syndrome)   U55017           (SEQ ID NO: 208)       209   CCCTGGGTTC       7.7   0.000   2.5   19.0   111334   ferritin, light polypeptide   M11147, M12938,           (SEQ ID NO: 209)       210   CAGCCTTGGA       7.3   0.007   0.4   3.2   65648   RNA binding motif protein 8   AA045586,           (SEQ ID NO: 210)                               AA188655,       211   ACCCTTCCCT   ·   7.3   0.007   0.4   3.2   99528   ESTs, Weakly similar to VON EBNER&#39;S   AA936288,           (SEQ ID NO: 211)                           GLAND PROTEIN PRECURSOR   AA977608,                                       ( H. sapiens )       212   GAGGGGAAAC       7.3   0.007   0.4   3.2   81972   SHC (Src homology 2 domain-containing)   AA767918, X68148,           (SEQ ID NO: 212)                           transforming protein 1       213   ACCCTTCCCT   ·   7.3   0.007   0.4   3.2   74564   signal sequence receptor, beta (translocon-   AW024384, D37991,           (SEQ ID NO: 213)                           associated protein beta)       214   ACTGGGTCTA       6.5   0.000   1.6   10.2   250871   non-metastatic cells 2, protein (NM23B)   AA514798,           (SEQ ID NO: 214)                           expressed in   AA828464,       215   TGGAGTGGAG       5.8   0.000   1.1   6.5   3764   guanylate kinase 1   F25667, AA024959,           (SEQ ID NO: 215)       216   CCCCTCCCTC   ·   5.5   0.008   0.7   3.7   79410   solute carrier family 4, anion exchanger,   AA741103,           (SEQ ID NO: 216)                           member 2 (erythrocyte membrane protein   AA767203,                                       band 3-)       217   CCCCTCCCTC   ·   5.5   0.008   0.7   3.7   74564   signal sequence receptor, beta (translocon-   AW083845           (SEQ ID NO: 217)                           associated protein beta)       218   ACAGTGGGGA       4.6   0.003   1.1   5.1   75839   zinc finger protein 6 (CMPXI)   AA740738,           (SEQ ID NO: 218)                               AA100363,       219   TGATTTCACT   ·   4.1   0.000   4.0   16.7   24322   ATPase, H+ transporting, lysosomal (vacuolar   AI065143           (SEQ ID NO: 219)                           proton pump) 9 kD       220   TTATGGGATC       4.0   0.000   3.4   13.5   5862   guanine nucleotide binding protein (G   M24194, AA480431,           (SEQ ID NO: 220)                           protein), beta polypeptide 2-like 1       221   ATAGACATAA       2.8   0.007   2.5   7.0   74614   complement component 1, q subcomponent   AI916184,           (SEQ ID NO: 221)                           binding protein   AA195312,       222   CACCTAATTG   ·   2.3   0.000   34.2   79.3   181368   U5 anRNP-specific protein (220 kD), ortholog   AW129234,           (SEQ ID NO: 222)                           of  S. cerevisiae  Prp8p   AW151854,       223   GAAATACAGT   ·   −1.8   0.006   18.6   10.2   79572   cathepain D (lysosomal aspartyl protease)   AA046688,           (SEQ ID NO: 223)                               AA063376,       224   GCCTTCCAAT       −2.0   0.004   15.9   7.9   76053   DEAD/H (Asp-Glu-Ala-Asp/His) box   AA030969,           (SEQ ID NO: 224)                           polypeptide 5 (RNA helicase, 68 kD)   AW019938,       225   GTGTGTTTGT       −2.0   0.005   15.0   7.4   118787   transforming growth factor, beta-induced,   M77349, AW021500,           (SEQ ID NO: 225)                           68 kD       226   AGCAGATCAG       −2.2   0.004   13.2   6.0   119301   S100 calcium-binding protein A10 (annexin II   AW022967,           (SEQ ID NO: 226)                           ligand, calpactin I, light polypeptide (p11))   AA009605,       227   CTGCCAAGTT       −2.6   0.003   10.3   3.7   75873   zyxin   AA040172,           (SEQ ID NO: 227)                               AA054721,       228   TTCTGTGAAT   ·   −3.7   0.002   8.5   2.3   182183   caldesmon 1   AA552208,           (SEQ ID NO: 228)                               AA652809,       229   CTTAATCCTG       −4.1   0.000   15.2   3.7   234433   ESTs, Weakly similar to transporter protein   AA864787,           (SEQ ID NO: 229)                           ( H. sapiens )   AW021494,       230   TCTCAATTCT   ·   −4.5   0.003   6.3   1.4   173497   Sec23 ( S. cerevisiae ) homolog B   AI581164,           (SEQ ID NO: 230)                               AW135796,       231   GCCCTTTCTC       −4.5   0.000   12.5   2.8   7835   endocytic receptor (macrophage mannose   AA126747,           (SEQ ID NO: 231)                           receptor family)   AA405572,       232   TCTCAATTCT   ·   −4.5   0.003   6.3   1.4   N/A   BB1   AA410935,           (SEQ ID NO: 232)                               AA022580,       233   TTCTTGTTTT       −5.3   0.006   4.9   0.9   74621   prion protein (p27-30) Creutzfeld-Jakob   D00015, M13687,           (SEQ ID NO: 233)                           disease, Gertsmann-Strausler-Scheinker                                       syndrome       234   TATGACTTAA   ·   −5.3   0.006   4.9   0.9   89230   potassium intermediate/small conductance   AA285078,           (SEQ ID NO: 234)                           calcium-activated channel, subfamily N,   AA491238,                                       member       235   GTTTTTTTTA   ·   −5.5   0.004   5.1   0.9   10114   ESTs, Weakly similar to protein B ( H. sapiens )   AA284721,           (SEQ ID NO: 235)                               AA496717,       236   GTCACAGTCC       −5.8   0.009   2.7   0.0   155321   serum response factor (c-los serum response   AA024483,           (SEQ ID NO: 236)                           element-binding transcription factor)   AA041538,       237   TAAGAAAATG       −8.3   0.008   2.9   0.0   75929   cadherin 11 (OB-cadherin, osteoblast)   AA258422,           (SEQ ID NO: 237)                               AA461076,       238   TTTTTTAAAA       −6.3   0.006   2.9   0.0   227400   mitogen-activated protein kinase kinase kinase   AA043537           (SEQ ID NO: 238)                           kinase 3       239   TTACTTATAC   ·   −8.8   0.004   3.1   0.0   159   tumor necrosis factor receptor superfamily,   AW138039           (SEQ ID NO: 239)                           member 1A       240   TTACTTATAC   ·   −8.8   0.004   3.1   0.0   29335   wingless-type MMTV integration site family,   AW129457           (SEQ ID NO: 240)                           member 2B       241   GCTGTTTTGT       −6.8   0.004   3.1   0.0   92186   KIAA0989 protein   AB023206,           (SEQ ID NO: 241)                               AA405541,       242   CTTTCTTTGA       −8.2   0.001   3.8   0.0   4909   regulated in glioma   AF052161,           (SEQ ID NO: 242)                               AA209488,       243   AAAAGATACT       −8.2   0.009   3.8   0.5   82071   Cbp/p300-interacting transactivator, with   AA115949,           (SEQ ID NO: 243)                           Glu/Asp-rich carboxy-terminal domain, 2   AA146987,       244   TCCGTGGTTG       −8.2   0.001   3.8   0.0   79516   brain acid-soluble protein 1   AF039656,           (SEQ ID NO: 244)                               AA602987,       245   CATTATAACT       −8.2   0.001   3.8   0.0   84359   hypothetical protein   AA806434,           (SEQ ID NO: 245)                               AA832337,       246   TGTCATCACA       −9.2   0.004   4.3   0.5   83354   lysyl oxidase-like 2   AA126278,           (SEQ ID NO: 246)                               AA149435,       247   TTTTGTTTTG   ·   −9.7   0.003   4.5   0.5   95583   transmembrane 4 superfamily member   AA037844,           (SEQ ID NO: 247)                            (tetraspan NET-7)   AA040421,       248   TACAGAGGGA       −10.1   0.002   4.7   0.5   3776   zinc finger protein 216   AA730188,           (SEQ ID NO: 248)                               AA814563,       249   AAGTGAAACA       −11.1   0.001   5.1   0.5   93659   protein disulfide isomerase related protein   AW411440           (SEQ ID NO: 249)                           (calcium-binding protein, intestinal-related)       250   AGTTTCCCAA       −13.0   0.000   6.0   0.5   75854   SULT1C sulfotransferase   AF055584,           (SEQ ID NO: 250)                               AA113827,       251   TACAATAAAC       −14.0   0.000   6.5   0.0   9071   progesterone membrane binding protein   AA836144,           (SEQ ID NO: 251)                               AJ002030,       252   CATATCATTA       −15.9   0.000   7.4   0.0   119205   insulin-like growth factor binding protein 7   AL036223,           (SEQ ID NO: 252)                               AA745836,           SECTION 7.                           EST clones of unknown function       253   GCACCTCAGC       14.5   0.000   0.0   3.2   10702   ESTs   AA027098,           (SEQ ID NO: 253)                               AA035781,       254   GAGAGAAAAT       14.5   0.000   0.0   3.2   181444   ESTs, Weakly similar to R12C12.6 ( C.     AA476914,           (SEQ ID NO: 254)                             elegans )   AA630706,       255   ACTTTTTAAA       14.1   0.000   1.1   15.8   157300   EST   AI365306           (SEQ ID NO: 255)       256   TTTCAGGGGA   ·   12.4   0.006   0.2   2.8   3804   DKFZP564C1940 protein   AA831451,           (SEQ ID NO: 256)                               AA070917,       257   TGATGGGCAT       12.4   0.006   0.2   2.8   74284   ESTs, Moderately similar to  S. cerevisiae     AI688503,           (SEQ ID NO: 257)                           hypothetical protein L3111 ( H. sapiens )   AI745361,       258   CTGGGCGTGT   ·   12.4   0.001   0.0   2.8   108948   ESTs, Weakly similar to laminin beta-2 chain   AA046403,           (SEQ ID NO: 258)                           precursor ( H. sapiens )   AA759123,       259   ACGGTGATGT       12.4   0.001   0.0   2.8   10453   ESTs   AA005401,           (SEQ ID NO: 259)                               AA045808,       260   CTGGGCGTGT   ·   12.4   0.001   0.0   2.8   15246   EST   T90794           (SEQ ID NO: 260)       261   TGAGGCCAGG   ·   8.3   0.010   0.0   1.9   110128   ESTs   AA584364           (SEQ ID NO: 261)       262   GGTTTGTGTG       8.3   0.010   0.0   1.9   83954     Homo sapiens  unknown mRNA   AF061739,           (SEQ ID NO: 262)                               AA732389,       263   TTGTGGGATC       8.3   0.010   0.0   1.9   167795   ESTs   AA018907,           (SEQ ID NO: 263)                               AA126960,       264   CCTGTACCCC   ·   6.3   0.010   0.0   1.9   12342     Homo sapiens  clone 24538 mRNA sequence   AI924428           (SEQ ID NO: 264)       265   TATGACCACA   ·   6.3   0.010   0.0   1.9   176577   ESTs   AI651376           (SEQ ID NO: 265)       266   ACTACCTTCA       8.3   0.010   0.0   1.9   9601   ESTs, Highly similar to CGI-106 protein ( H.     AA744772,           (SEQ ID NO: 266)                             sapiens )   AA805690,       267   CTGCTGTGAT   ·   8.3   0.010   0.0   1.9   193909   ESTs, Weakly similar to IIII ALU   AA628209,           (SEQ ID NO: 267)                           SUBFAMILY SC WARNING ENTRY IIII   AI690704,                                       ( H. sapiens )       268   GAGTGAGTGA   ·   7.3   0.007   0.4   3.2   52186   ESTs, Weakly similar to IIII ALU   H62203           (SEQ ID NO: 268)                           SUBFAMILY J WARNING ENTRY IIII ( H.                                           sapiens )       269   GAGTGAGTGA   ·   7.3   0.007   0.4   3.2   10483   ESTs, Weakly similar to C44C1.2 gene   AA009696,           (SEQ ID NO: 269)                           product ( C. elegans )   AA088448,       270   TTTGTTAAAA   ·   4.1   0.007   1.1   4.6   111244   ESTs   AA748351,           (SEQ ID NO: 270)                               AA769191,       271   AAGATAATGC   ·   4.1   0.007   1.1   4.6   102898   ESTs, Weakly similar to C11D2.4 ( C.     AA806449,           (SEQ ID NO: 271)                           elegans)   AA115687,       272   AAGATAATGC   ·   4.1   0.007   1.1   4.6   251978   EST   C14037           (SEQ ID NO: 272)       273   TTTGTTAAAA   ·   4.1   0.007   1.1   4.6   207118   EST   AI806514           (SEQ ID NO: 273)       274   AGGAAAGCTG       4.0   0.000   6.3   25.0   76437   DKFZP566B023 protein   AA523344,           (SEQ ID NO: 274)                               AA551986,       275   CAAGCATCCC       3.5   0.000   5.8   20.4   153423   ESTs   AW275649,           (SEQ ID NO: 275)                               AW276934,       276   GAAATACAGT   ·   −1.8   0.006   18.6   10.2   67201   ESTs   AA122047,           (SEQ ID NO: 276)                               AA404659,       277   TTCTGTGAAT   ·   −3.7   0.002   8.5   2.3   77870   ESTs   AA022926,           (SEQ ID NO: 277)                               AA121431,       278   GAAATAATGG   ·   −4.0   0.001   9.2   2.3   178053   ESTs   AA412270,           (SEQ ID NO: 278)                               AI208372,       279   GAAATAATGG   ·   −4.0   0.001   9.2   2.3   209037   ESTs   AI143898, AI808260           (SEQ ID NO: 279)       280   TATGACTTAA   ·   −5.3   0.006   4.9   0.9   203352   ESTs   W52993           (SEQ ID NO: 280)       281   GTAAGATTAG   ·   −5.8   0.000   8.1   1.4   250705   ESTs   AA953513,           (SEQ ID NO: 281)                               AI129290,       282   GCCATATTAT       −5.8   0.009   2.7   0.0   19280   KIAA0544 protein   R70600, AI081100,           (SEQ ID NO: 282)       283   AATTTTCATT   ·   −6.3   0.006   2.9   0.0   77695   KIAA0008 gene product   AI889277           (SEQ ID NO: 283)       284   AATTTTCATT   ·   −6.3   0.006   2.9   0.0   35092   ESTs   AA343561,           (SEQ ID NO: 284)                               AA449315,       285   TTCCTCCTTT   ·   −7.7   0.002   3.6   0.0   226144   ESTs   AI215617,           (SEQ ID NO: 285)                               AI982565,       286   GCTTGTCTTT       −7.7   0.002   3.6   0.0   224620   ESTs   AI560377, AI953171           (SEQ ID NO: 286)       287   ACAGTGTTAA       −7.7   0.002   3.6   0.0   166342   ESTs   AA167571,           (SEQ ID NO: 287)                               AA653213,       288   TTCCTCCTTT   ·   −7.7   0.002   3.6   0.0   115581   EST, Highly similar to KIAA0826 protein ( H.     AA463908           (SEQ ID NO: 288)                             sapiens )       289   TTTTGTTTTG   ·   −9.7   0.003   4.5   0.5   74867   ESTs   AA120954,           (SEQ ID NO: 289)                               AA489661,       290   ACAGATTTGA       −10.1   0.000   4.7   0.0   41271   ESTs   AA253217,           (SEQ ID NO: 290)                               AA593446,       291   TTCCCCCTTC       −10.6   0.000   4.9   0.0   163928   ESTs   AA577100,           (SEQ ID NO: 291)                               AI819034       292   AAAGTCATTG   ·   −11.1   0.001   5.1   0.5   21145   Human BAC clone RGOB3M05 from 7q21-7q22   AI056386, AI161119           (SEQ ID NO: 292)           SECTION 8.                           UNIDENTIFIED TRANSCRIPTS       293   CCGCCGAAGT       24.9   0.000   0.0   5.6           (SEQ ID NO: 293)       294   ACCTTTTCAA       16.6   0.000   0.0   3.7           (SEQ ID NO: 294)       295   GCCCCTCCGG       16.6   0.001   0.2   3.7           (SEQ ID NO: 295)       296   GCTTTCTCAC       10.4   0.000   0.9   9.3           (SEQ ID NO: 296)       297   CGCCGCGGCT       10.4   0.004   0.0   2.3           (SEQ ID NO: 297)       298   GTGACCACGG       9.3   0.001   0.4   4.2           (SEQ ID NO: 298)       299   GTTAACAGTC       8.3   0.010   0.0   1.9           (SEQ ID NO: 299)       300   GCCGTTCTTA       8.3   0.010   0.0   1.9           (SEQ ID NO: 300)       301   AGGCTACCGG       7.3   0.007   0.4   3.2           (SEQ ID NO: 301)       302   ACTTTTTCAC       5.4   0.000   1.8   9.7           (SEQ ID NO: 302)       303   TCCCCGTCAT       −4.5   0.003   6.3   1.4           (SEQ ID NO: 303)       304   AGGAATGTTA       −5.1   0.003   4.7   0.9           (SEQ ID NO: 304)       305   TCCCTTATTA       −5.3   0.005   4.9   0.9           (SEQ ID NO: 305)       306   TCTTGATATT       −5.8   0.009   2.7   0.0           (SEQ ID NO: 306)       307   AAGGCAATTT       −6.8   0.001   6.3   0.9           (SEQ ID NO: 307)       308   TTCGGTTGGT       −7.2   0.000   10.1   1.4           (SEQ ID NO: 308)       309   TCCCCGGTAC       −7.5   0.000   13.9   1.9           (SEQ ID NO: 309)       310   GCTGACGTCA       −8.2   0.001   3.8   0.0           (SEQ ID NO: 310)       311   TCCCCCGTAC       −8.7   0.001   4.0   0.0           (SEQ ID NO: 311)       312   ACGTTCTCTT       −9.2   0.001   4.3   0.0           (SEQ ID NO: 312)       313   TAACTTTTGG       −9.2   0.001   4.3   0.0           (SEQ ID NO: 313)       314   AAATGCTTGG       −9.7   0.003   4.5   0.5           (SEQ ID NO: 314)       315   CTAAAAACCT       −10.1   0.000   4.7   0.0           (SEQ ID NO: 315)       316   GTGAGAGTTT       −12.1   0.000   5.6   0.5           (SEQ ID NO: 316)       317   GGTGGACACG       −13.0   0.000   6.0   0.0           (SEQ ID NO: 317)       318   TCCCCTATTA       −15.4   0.000   7.2   0.0           (SEQ ID NO: 318)       319   CTTTATTCCA       −18.3   0.000   17.0   0.9           (SEQ ID NO: 319)                    
         [0208]    [0208]                                                                                             No   Tag_Sequence   SHEP-2   SHEP-21N   P value   Unigene cluster   Unigene description   Accession code                                1   CGACGAGGAG SEQ ID NO: 320   1.8   7.0   0.0087   9999   epithelial membrane protein 3           2   TTTAAAAAAA* SEQ ID NO: 321   21.7   7.0   0.0003   97437   centriole associated protein       3   GAATAAATGT SEQ ID NO: 322   7.2   1.2   0.0053   8762   FK506-binding protein 9 (63 kD)   AI088246       4   TAAAATAAAA* SEQ ID NO: 323   5.0   0.0   0.0027   87100   ESTs       5   TCTTCTGCCA SEQ ID NO: 324   9.5   1.7   0.0021   86392   ESTs       6   TGCTTTGGGA SEQ ID NO: 325   1.4   5.8   0.0100   84344   ESTs, Highly similar to CGI-135 protein [ H. sapiens ]   AA788733       7   GGGCGCTGTG SEQ ID NO: 326   0.9   6.4   0.0020   8372   ubiquinol-cytochrome c reductase (6.4 kD) subunit       8   TTAGATAAGC* SEQ ID NO: 327   4.5   12.2   0.0036   82916   chaperonin containing TCP1, subunit 6A (zeta 1)       9   AGCTCTCCCT SEQ ID NO: 328   29.3   53.4   0.0000   82202   ribosomal protein L17   AA961432       10   CCCTGCCTTG SEQ ID NO: 329   0.0   3.5   0.0052   82045   midkine (neurite growth-promoting factor 2)       11   GCACAAGAAG SEQ ID NO: 330   9.5   19.2   0.0037   81634   ATP synthase, H+ transporting, mitochondrial F0 complex, subunit b, isoform 1       12   TTAAAGGCCG SEQ ID NO: 331   0.5   5.2   0.0025   79086   ribosomal protein, mitochondrial, L3       13   AGAAAGATGT SEQ ID NO: 332   9.5   20.3   0.0016   78225   annexin A1   AA846272       14   TTTAAAAAAA* SEQ ID NO: 333   21.7   7.0   0.0003   77501   sarcoglycan, beta (43 kD dystrophin-associated glycoprotein)       15   GTAAAAAAAA* SEQ ID NO: 334   44.7   20.9   0.0002   77495   UBX Domain-containing 1   AI492365       16   CTTGATTCCC SEQ ID NO: 335   0.9   6.4   0.0020   77266   qulescin Q6       17   TGTGCTCGGG SEQ ID NO: 336   2.3   7.6   0.0091   76847   KIAA0088 protein       18   CAGTCTCTCA SEQ ID NO: 337   0.9   7.0   0.0010   76230   ribosomal protein S10       19   TACGTACTGC SEQ ID NO: 338   0.0   3.5   0.0052   76086   ESTs, Highly, similar to small zinc finger-like protein [ H. sapiens ]       20   GGCAAGCCCC SEQ ID NO: 339   9.9   40.1   0.0000   76067   heat shock 27 kD protein 1   AI540836       21   CGGCTGAATT SEQ ID NO: 340   0.9   5.8   0.0043   75888   phosphogluconate dehydrogenase       22   GGCTGGGGGC SEQ ID NO: 341   19.4   38.3   0.0001   75721   profilin 1   AA903097       23   TGCTGGGTGG* SEQ ID NO: 342   0.5   4.6   0.0056   754   folylpolyglutamate synthase       24   TCAGATCTTT SEQ ID NO: 343   39.7   70.9   0.0000   75344   ribosomal protein S4, X-linked   AA954645       25   AAGAGTTTTG SEQ ID NO: 344   0.5   5.8   0.0010   75313   aido-keto reductase family 1, member B1 (aldose reduclase)       26   ACAAATCCTT SEQ ID NO: 345   1.8   7.0   0.0087   752   FK506-binding protein 1A (12 kD)       27   AATATGTGGG SEQ ID NO: 346   5.4   12.8   0.0060   74649   cytochrome c oxidase subunit Vlc   AI025170       28   GGGTTTTTAT SEQ ID NO: 347   5.0   11.6   0.0100   74497   nuclease sensitive element binding protein 1       29   TCTGCTTACA SEQ ID NO: 348   2.7   8.1   0.0093   74267   ribosomal protein L15       30   TTTAAAAAAA* SEQ ID NO: 349   21.7   7.0   0.0003   74088   early growth response 3       31   CAAACCATCC* SEQ ID NO: 350   1.4   5.8   0.0100   65114   keratin 18       32   CAGACTTTTG* SEQ ID NO: 351   5.9   12.8   0.0100   63348   DKFZP586M121 protein       33   TTGGGGTTTC SEQ ID NO: 352   40.6   74.9   0.0000   62954   ferritin, heavy polypeptide 1   AA866040       34   AAGCCTTGCT SEQ ID NO: 353   5.4   0.6   0.0098   6289   growth factor receptor-bound protein 2 [No, now described as small stress protein-like   AI039721                               protein HSP22       35   AAGAAACCTT SEQ ID NO: 354   1.4   5.8   0.0100   5836   ESTs, Highly similar to CGI-138 protein [ H. sapiens ]       36   AAGGAAATGA SEQ ID NO: 355   4.5   0.0   0.0043   57929   sllt (Drosophila) homolog 3   AI741785       37   AACTAAAAAA* SEQ ID NO: 356   68.6   91.8   0.0010   55921   glutamyl-prolyl-tRNA synthetase       38   ATAATTCTTT SEQ ID NO: 357   73.1   102.8   0.0001   539   ribosomal protein S29       39   GTAAAAAAA* SEQ ID NO: 358   44.7   20.9   0.0002   460   Activating Transcription Factor 3   AA903193       40   TTTTAAAAAT* SEQ ID NO: 359   7.7   1.7   0.0100   45033   lacrimal proline rich protein       41   CTCGAATAAA SEQ ID NO: 360   4.5   0.0   0.0043   34871   KIAA0569 gene product   AI338485       42   AACTAAAAAA* SEQ ID NO: 361   68.6   91.8   0.0010   3297   ribosomal protein S27a       43   GAGGCGATCA SEQ ID NO: 362   0.0   3.5   0.0052   30783   ESTs, Weakly similar to eyelld [ D. melanogaster ]       44   GTGGCTGAAA SEQ ID NO: 363   5.0   0.0   0.0027   29797   ribosomal protein L10   AI582446       45   GTTTCCCCAA* SEQ ID NO: 364           0.0067   281434       46   GGTGAAGACA SEQ ID NO: 365   8.6   1.2   0.0015   26951   Human mRNA for KIAA0375 gene, complete cds   AI080611       47   GCATTTAAAT* SEQ ID NO: 366   16.7   27.3   0.0065   250876   eukaryotic translation elongation factor 1 beta 2       48   TTTTGTATTT SEQ ID NO: 367   5.9   0.6   0.0055   250705   ESTs       49   CAGACTTTTG* SEQ ID NO: 368   5.9   12.8   0.0100   250501   TNF? elastin microfibril interface located protein       50   GATCCCAACA SEQ ID NO: 369   0.5   4.6   0.0056   25   ATP synthase, H+ transporting, mitochondrial F1 complex, beta polypeptide       51   CTGTTGATTG SEQ ID NO: 370   16.3   26.7   0.0070   249495   heterogeneous nuclear ribonucleoprotein A1       52   CACGCAATGC* SEQ ID NO: 371   0.5   5.8   0.0010   244   amino-terminal enhancer of split   AI015996       53   TGGTACACGT SEQ ID NO: 372   0.9   5.8   0.0043   242463   keratin 8       54   TTTTAAAAAT* SEQ ID NO: 373   7.7   1.7   0.0100   240013   catechol-O-methyltransferase       55   ATTCTCCAGT SEQ ID NO: 374   48.8   72.6   0.0002   234518   ribosomal protein L23       56   CCCTTAGCTT SEQ ID NO: 375   13.5   3.5   0.0011   233936   myosin, light polypeptide, regulatory, non-sarcomeric (20 kD)   AI033904       57   GTGGTGGGCG* SEQ ID NO: 376   0.9   7.0   0.0010   233694   ESTs, Weakly similar to ZK1058.5 [ C. elegans ]       58   GCGGGGTACC SEQ ID NO: 377   1.4   5.8   0.0100   227823   pM5 protein       59   GGAGAGTACA SEQ ID NO: 378   0.0   3.5   0.0052   225939   slalyltransferase 9 (CMP-NeuAc:lactosylceramide alpha-2,3-slalyltransferase; GM3                               synthase)       60   TAAAATAAAA* SEQ ID NO: 379   5.0   0.0   0.0027   21254   TRAF Interacting protein       61   GTGGTGGGCG* SEQ ID NO: 380   0.9   7.0   0.0010   209741   EST       62   GTGGTGGGCG* SEQ ID NO: 381   0.9   7.0   0.0010   208985   ESTs       63   TCCAAATCGA SEQ ID NO: 382   6.8   1.2   0.0080   2064   vimentin       64   TAAAATAAAA* SEQ ID NO: 383   5.0   0.0   0.0027   204144   ESTs, Moderately similar to tumor necrosis factor-alpha-induced protein B12 [ H. sapiens ]       65   TAAAATAAAA* SEQ ID NO: 384   5.0   0.0   0.0027   202218   EST       66   TTCAATAAAA* SEQ ID NO: 385   58.7   93.0   0.0000   2012   transcobalamin I (vitamin B12 binding protein, R binder family)   AI738761       67   TGCTGGGTGG* SEQ ID NO: 386   0.5   4.6   0.0056   198273   NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 8 (19 kD, ASHI)       68   TAAAATAAAA* SEQ ID NO: 387   5.0   0.0   0.0027   190401   ESTs, Weakly similar to predicted using Genefinder [ C. elegans ]       69   AAGGTCGAGC SEQ ID NO: 388   1.8   7.0   0.0087   184582   ribosomal protein L24       70   GCATAATAGG SEQ ID NO: 389   31.6   54.0   0.0001   184108   ribosomal protein L21   AI224420       71   GTAAAAAAAA* SEQ ID NO: 390   44.7   20.9   0.0002   183842   Ubiquitin B   AA988708       72   TAATATTTTT SEQ ID NO: 391   11.7   2.9   0.0020   182485   actinin, alpha 4       73   GAAAAATGGT SEQ ID NO: 392   48.3   87.7   0.0000   181357   laminin receptor 1 (67 kD, ribosomal protein SA)   AI025931       74   AGAACCTTAA SEQ ID NO: 393   5.0   0.0   0.0027   181244   major histocompatibility complex, class I, A   AI023950       75   CTCATAAGGA SEQ ID NO: 394   49.2   70.9   0.0006   181165   eukaryotic translation elongation factor 1 alpha 1       76   TAATTTTGGA SEQ ID NO: 395   9.0   17.4   0.0078   180152   ESTs       77   CAATAAATGT SEQ ID NO: 396   37.0   57.5   0.0004   179779   ribosomal protein L37       78   TTCAATAAAA* SEQ ID NO: 397   58.7   93.0   0.0000   177592   ribosomal protein, large, P1   AA961386       79   TTAAATAGCA SEQ ID NO: 398   6.8   0.6   0.0021   172928   collagen, type I, alpha 1   AA992596       80   GGAGGAGAGC SEQ ID NO: 399   5.0   0.0   0.0027   172928   collagen, type I, alpha 1       81   TGAAATTGTC SEQ ID NO: 400   4.5   0.0   0.0043   172928   collagen, type I, alpha 1       82   AATGCAGGCA SEQ ID NO: 401   1.4   6.4   0.0067   172673   S-adenosylhomocysteine hydrolase   AI051370       83   TTCCGGTTCC SEQ ID NO: 402   9.0   1.7   0.0030   172609   nucleobindin 1   AI025019       84   CACGCAATGC* SEQ ID NO: 403   0.5   5.8   0.0010   170683   EST   AI015996       85   TAGACTTATT SEQ ID NO: 404   0.5   4.6   0.0056   170197   glutamic-oxaloacetic transaminase 2, mitochondrial (aspartate aminotransferase 2)       86   TTCACAGTGG SEQ ID NO: 405   0.5   5.2   0.0025   169992   protein phosphatase 3 (formerly 2B), regulatory subunit B (19 kD), alpha isoform                               (calcineurin B, type I)       87   TGCACGTTTT SEQ ID NO: 406   37.5   61.0   0.0001   169793   ribosomal protein L32   AA922605       88   GCAGCTCAGG SEQ ID NO: 407   2.3   7.6   0.0091   167137   ESTs, Moderately similar to CATHEPSIN D PRECURSOR [ H. sapiens ]       89   GGTGAGACAC SEQ ID NO: 408   2.7   8.7   0.0071   164280   solute carrier family 25 (mitochondrial carrier; adenine nucleotide translocator), member 6       90   TTTAAAAAAA* SEQ ID NO: 409   21.7   7.0   0.0003   155545   37 kDa leucine-rich repeat (LRR) protein       91   ATGTCATCAA SEQ ID NO: 410   1.4   7.0   0.0030   152936   adaptor-related protein complex 2, mu 1 subunit       92   TAATAAAGGT SEQ ID NO: 411   45.1   62.2   0.0029   151604   ribosomal protein S8   AI312878       93   TTAAAACAAA SEQ ID NO: 412   4.1   0.0   0.0070   150508   ESTs   AI280093       94   TGGCCTAAAA SEQ ID NO: 413   4.5   0.0   0.0043   1501   syndecan 2 (heparan sulfate proteoglycan 1, cell surface-associated, fibroglycan)   AI005403       95   GGTTAATTGA SEQ ID NO: 414   4.1   0.0   0.0070   14376       AI590977       96   TTCAATAAAA* SEQ ID NO: 415   58.7   93.0   0.0000   141269   ESTs   AA961386       97   ATGTGAAGAA SEQ ID NO: 416   6.8   1.2   0.0080   13662     Homo sapiens  clone 25036 mRNA sequence   AI279223       98   TTTAAAAAAA* SEQ ID NO: 417   21.7   7.0   0.0003   134533   ESTs       99   TTAGATAAGC* SEQ ID NO: 418   4.5   12.2   0.0036   134350   ESTs       100   GTGACAGAAG SEQ ID NO: 419   5.4   13.4   0.0034   129673   eukaryotic translation Initiation factor 4A, Isoform 1       101   CTGGGTTAAT SEQ ID NO: 420   42.4   77.8   0.0000   126701   ribosomal protein S19   AA865047       102   CAAACCATCC* SEQ ID NO: 421   1.4   5.8   0.0100   125170   ESTs       103   GGGACTGGGC* SEQ ID NO: 422   0.5   5.2   0.0025   122256   ESTs       104   GCATTTAAAT* SEQ ID NO: 423   16.7   27.3   0.0065   120979   ESTs       105   TAGGTTGTCT SEQ ID NO: 424   55.1   71.5   0.0057   119252   tumor protein, translationally-controlled 1   AA808956       106   GACGTGTGGG SEQ ID NO: 425   0.0   4.6   0.0009   119192   H2A histone family, member Z       107   GGCTTTACCC SEQ ID NO: 426   9.0   20.9   0.0006   119140   eukaryotic translation initiation factor 5A       108   AACTAATACT SEQ ID NO: 427   4.5   12.8   0.0022   118724   DR1-associated protein 1 (negative cofactor 2 alpha)   AI028098       109   TAAAATAAAA* SEQ ID NO: 428   5.0   0.0   0.0027   118246   ESTs       110   GGGACTGGGC* SEQ ID NO: 429   0.5   5.2   0.0025   117848   hemoglobin, epsilon 1       111   TAAAAACAAA SEQ ID NO: 430   5.4   0.6   0.0098   114599       AW029321, W1923       112   GTTTCCCCAA* SEQ ID NO: 431   1.4   6.4   0.0067   112423     Homo sapiens  mRNA; cDNA DKFZp586l1420 (from clone DKFZp586l1420)       113   GCAAAAAAAA SEQ ID NO: 432   67.3   31.4   0.0000   11221   ESTs, Weakly similar to fos39554_1 [ H. sapiens ]   AI057027       114   CCAGAACAGA SEQ ID NO: 433   37.5   55.8   0.0011   111222   ribosomal protein L30       115   GTACGGAGAT SEQ ID NO: 434   0.5   4.6   0.0056   109225   vascular cell adhesion molecule 1       116   GTTTCCCCAA* SEQ ID NO: 435   1.4   6.4   0.0067   107573   sialyltransferase       117   GGCCCCTCAC SEQ ID NO: 436   0.5   4.6   0.0056   106283   Insulin-like growth factor binding protein 6       118   TTTAAAAAAA* SEQ ID NO: 437   21.7   7.0   0.0003   108204   ESTs, Moderately similar to antigen containing epitope to monoclonal antibody MMS-                               85/12 [ M. musculus ]       119   CCTCCCCCGT SEQ ID NO: 438   0.9   5.2   0.0092   10488   Breakpoint cluster region protein, uterine lelomyoma, 1; barrier to autointegration factor       120   AGCAGGGCTC SEQ ID NO: 439   0.0   5.2   0.0004   100623   phospholipase C, beta 3, neighbor pseudogene       121   AATTGCAAGC SEQ ID NO: 440   5.0   0.0   0.0027   —       U50523       122   TTTAACGGCC SEQ ID NO: 441   43.8   12.8   0.0000   —       AA196553       123   CATTGCCTTC SEQ ID NO: 442   5.9   0.6   0.0055   —       124   GCTTGCTGCC SEQ ID NO: 443   4.5   0.0   0.0043   —       125   AAAACATTCT SEQ ID NO: 444   67.7   32.5   0.0000   —       AI538076       126   GCAGACATTG SEQ ID NO: 445   0.9   5.8   0.0043   —       127   ACCCTTGGCC SEQ ID NO: 446   12.2   26.7   0.0003   —       128   AGTAGGTGGC SEQ ID NO: 447   8.1   1.7   0.0068   —   U5 snRNP-specific protein (220 kD), ortholog of  S. cerevisiae  Prp8p       129   GCAAGCCAAC SEQ ID NO: 448   16.7   33.1   0.0002   —   actinin, alpha 1   AI669642       130   TTAGCTTGTT SEQ ID NO: 449   4.1   0.0   0.0070   —       131   GTAATAACTT SEQ ID NO: 450   4.1   0.0   0.0070   —       132   CGCCGTCGGC SEQ ID NO: 451   0.0   3.5   0.0052   —       133   ACTCTTTCAA SEQ ID NO: 452   0.5   4.6   0.0056   —       134   TGCTACGAAA SEQ ID NO: 453   5.9   0.6   0.0055   —       135   CCCCGGTACA SEQ ID NO: 454   7.2   1.2   0.0053   —       136   TTATAAAAGA SEQ ID NO: 455   10.8   3.5   0.0098   —