HUMAN POLYHOMEOTIC 1(hphl) ACTS AS A TUMOR SUPPRESSOR

Abstract: A novel human tumor suppressor gene termed polyhomeotic 1 is disclosed. The human polyhomeotic 1 gene and protein can be used as therapeutic and diagnostic tools for proliferative and developmental disorders. The gene can also be used to identify a p13 region of human chromosome 12.

Description: HUMAN POLYHOMEOTIC 1 (hphl) ACTS AS A TUMOR SUPPRESSOR This application claims the benefit of the following copending provisional applications: Serial No. 60/024,349, filed August 23, 1996, Serial No. 60/031,569, filed December 4, 1996, and Serial No. 60/036,939, filed February 6, 1997, each of which is incorporated by reference herein. TECHNICAL AREA OF THE TNVENTION The invention relates to the area of tumor suppression. More particularly, the invention relates to tumor suppressor genes and proteins. BACKGROUND OF THE INVENTION Mutations in tumor suppressor genes play an important role in the development of neoplasias. Manipulation of tumor suppressor gene expression can be used to prevent or treat neoplasias. Detection of mutations in tumor suppressor genes can also be used to detect neoplastic cells and genetic predispositions to neoplasias. Thus, there is a need in the art for the identification of mammalian tumor suppressor genes which can be used in methods of diagnosing, prognosing, and treating neoplastic cells in humans and other mammals. SUMMARY OF THE INVENTION It is an object of the invention to provide an isolated and purified human polyhomeotic 1 protein. It is another object of the invention to provide an isolated and purified human polyhomeotic 1 polypeptide. It is yet another object of the invention to provide an hphl fusion protein. It is still another object of the invention to provide a preparation of antibodies. It is yet another object of the invention to provide an isolated and purified subgenomic polynucleotide. It is still another object of the invention to provide an expression construct for expressing all or a portion of a human polyhomeotic 1 protein. It is a fiirther object of the invention to provide a homologously recombinant cell comprising a DNA construct. It is even another object of the invention to provide a method of identifying neoplastic tissue of a human. It is another object of the invention to provide a method to aid in the diagnosis or prognosis of neoplasia in a human. It is yet another object of the invention to provide a method to aid in detecting a genetic predisposition to neoplasia in a human. It is still another object of the invention to provide a method of identifying a human chromosome 12. It is even another object of the invention to provide a therapeutic composition for restoring a wild-type human polyhomeotic 1 function to a cell which lacks that function. It is another object of the invention to provide a method of treating proliferative disorders. It is still another object of the invention to provide a method of inducing a cell to differentiate. These and other objects of the invention are provided by one or more of the embodiments described below. One embodiment of the invention provides an isolated and purified human polyhomeotic 1 protein. The isolated and purified human polyhomeotic 1 has the amino acid sequence shown in SEQ ID NO:2. Another embodiment of the invention provides an isolated and purified human polyhomeotic 1 polypeptide. The isolated and purified human polyhomeotic 1 polypeptide. consists of at least 22 contiguous amino acids selected from the amino acid sequence shown in SEQ ID NO:2. Yet another embodiment of the invention provides an hphl fusion protein. The hphl fusion protein comprises a first protein segment and a second protein segment fused together by means of a peptide bond. The first protein segment consists of at least 8 contiguous amino acids of a human polyhomeotic 1 protein. Still another embodiment of the invention provides a preparation of antibodies which specifically bind to a human polyhomeotic 1 protein. Even another embodiment of the invention provides an isolated and purified subgenomic polynucleotide. The isolated and purified subgenomic polynucleotide consists of at least 10 contiguous nucleotides selected from the nucleotide sequence shown in SEQ ID NO: 1. Yet another embodiment of the invention provides an expression construct for expressing all or a portion of a human polyhomeotic 1 protein. The expression construct comprises a promoter and a polynucleotide segment. The polynucleotide segment encodes at least 8 contiguous amino acids of a human polyhomeotic 1 protein. The polynucleotide segment is located downstream from the promoter. Transcription of the polynucleotide segment initiates at the promoter. A further embodiment of the invention provides a homologously recombinant cell. The homologously recombinant cell comprises an incorporated new transcription unit wherein the new transcription unit comprises an exogenous regulatory sequence, an exogenous exon, and a splice donor site. The transcription unit is located upstream of a coding sequence of an hphl gene. The exogenous regulatory sequence directs transcription of the coding sequence of the hphl gene. The new transcription unit is incorporated into the genome using segments of homologous DNA from the hphl gene. The new transcription unit can be used to turn the hphl gene on or off as desired. Still another embodiment of the invention provides a method of identifying a neoplastic tissue of a human. The method comprises comparing the expression of a polyhomeotic 1 gene in a first tissue of a human suspected of being neoplastic with the expression of a polyhomeotic 1 gene in a second tissue of the human which is normal. Underexpression of the human polyhomeotic 1 gene in the first tissue identifies the first tissue as being neoplastic. Even another embodiment of the invention provides a method to aid in the diagnosis or prognosis of neoplasia in a human. The method comprises comparing a polyhomeotic 1 gene, mRNA or protein in a first tissue of a human suspected of being neoplastic with a polyhomeotic 1 gene, mRNA, or protein in a second tissue of a human which is normal. A difference between the polyhomeotic 1 genes, mRNAs, or proteins in the first and second tissues indicates neoplasia in the first tissue. Another embodiment of the invention provides a method to aid in detecting a genetic predisposition to neoplasia in a human. The method comprises comparing a polyhomeotic 1 gene, mRNA or protein in the fetal tissue of a human with a wild-type human polyhomeotic 1 gene, mRNA or protein. A difference between the polyhomeotic 1 gene, mRNA or protein in the fetal tissue of the human and the wild- type human polyhomeotic 1 gene, mRNA or protein indicates a genetic predisposition to neoplasia in the human. Yet another embodiment of the invention provides method of identifying a human chromosome 12. The method comprises the steps of contacting a preparation of metaphase human chromosomes with a nucleotide probe comprising at least 12 contiguous nucleotides selected from the nucleotide sequence shown in SEQ ID NO: 1 and detecting a region of a chromosome which specifically hybridizes to the nucleotide probe. A region of a chromosome which specifically hybridizes to the nucleotide probe is identified as a region of human chromosome 12. Even another embodiment of the invention provides a therapeutic composition for restoring a wild-type human polyhomeotic 1 function to a cell which lacks that function. The therapeutic composition comprises all or a portion of a wild-type human polyhomeotic 1 gene or expression product and a pharmaceutically acceptable carrier. Said all or a portion of the wild-type human polyhomeotic 1 gene or expression product is capable of restoring a wild-type polyhomeotic 1 function to a cell. Still another embodiment of the invention provides a method of treating proliferative disorders. The method comprises the step of administering to a human a composition comprising all or a portion of a wild-type human polyhomeotic 1 gene or expression product. Said all or a portion of the wild-type human polyhomeotic 1 gene or expression is capable of restoring or enhancing a wild-type polyhomeotic 1 function to a cell. A further embodiment of the invention provides a method of inducing a cell to differentiate. The method comprises the step of contacting a progenitor cell with a composition comprising all or a portion of a human polyhomeotic 1 gene or expression product. Said all or a portion of the human polyhomeotic 1 gene or expression product is capable of inducing differentiation of the cell. The present invention thus provides the art with a novel human tumor suppressor gene, called "polyhomeotic 1" (hphl). The hphl gene and protein can be used, inter alia, as therapeutic and diagnostic tools for proliferative and developmental disorders and to identify a pl3 region of a human chromosome 12. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1. Northern blots probed with an hphl nucleotide probe. The figure depicts hphl mRNA expression in human tissues and cancer cell lines. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS It is a discovery of the present invention that hphl functions as a tumor suppressor and thus is implicated in neoplasias and other proliferative disorders, such as dysplasias and hypeφlasias. The hphl gene, protein, and mRNA can be used as a diagnostic and therapeutic tool for these disorders. Coding sequences of hphl can also be used to identify human chromosome 12. The coding region of the hphl gene has the nucleotide sequence shown in SEQ ID NO: 1. Other (degenerate) sequence encoding the same amino acid sequence and those nucleotide sequences which vary by up to 10% are included herein. Typically these can be confirmed by hybridization under stringent conditions. The hphl gene maps to human chromosome 12pl3, a region frequently lost in non-small cell lung cancer and breast cancer. While not wanting to be bound by any particular theory, it is believed that there are lethal alleles of hphl which are involved in neoplasias, such as non-small cell lung carcinoma, breast cancer, lymphoma, melanoma, or adenocarcinoma. In addition, it is believed that hphl is involved in dyplastic disorders, such as cervical epithelial dysplasia, and hypeφlastic disorders, such as breast, prostate, or thyroid hypeφlasias. Human polyhomeotic 1 protein has the amino acid sequence shown in SEQ ID NO:2. Any naturally occurring variants of this sequence that may occur in human tissues and which have tumor suppressive or antiproliferative activity are within the scope of this invention. Thus, reference herein to either the nucleotide or amino acid sequence of hphl includes reference to naturally occurring variants of these sequences. Nonnaturally occurring variants which differ by as much as four amino acids and retain biological function are also included here. Preferably the changes are conservative amino acid changes, i.e., changes of similarly charged or uncharged amino acids. Human polyhomeotic 1 mRNA comprises two major transcripts which measure 4.4 kb and 6.5 kb on Northern blots of human polyA+ RNA probed with an hphl nucleotide probe (Figure 1). The 4.4 and 6.5 kb transcripts are expressed, inter alia, at highest levels in adult thymus and testis; at lower levels in the heart, prostate, ovary, small intestine, peripheral blood lymphocytes, skeletal muscle, and pancreas; and at very low levels in the lung, liver, and kidney. The 4.4 and 6.5 kb hphl mRNA transcripts are also expressed in human cancer cell lines, such as SW480 (colon carcinoma), G361 (melanoma), and Burkitt's lymphoma Raji. Human polyhomeotic 1 polypeptides comprise at least 22, 25, 30, or 35 contiguous amino acids of the amino acid sequence shown in SEQ ID NO:2. Both full-length hphl protein and hphl polypeptides are useful for generating antibodies against hphl amino acid sequences. Human polyhomeotic 1 proteins and polypeptides can be isolated and purified from human cells such as thymus, testis, heart, prostate, ovary, small intestine, peripheral blood lymphocytes, skeletal muscle, pancreas, lung, liver, and kidney. Preferably, the protein or polypeptides are purified from thymus or testis. Polyhomeotic 1 proteins or polypeptides can be purified by any method known in the art. These methods include, but are not limited to, size exclusion chromatography, ammonium sulfate fractionation, ion exchange chromatography, affinity chromatography, crystallization, electrofocusing, and preparative gel electrophoresis. The skilled artisan can readily select methods which will result in a preparation of hphl protein or polypeptide which is substantially free from other proteins and from carbohydrates, lipids, or subcellular organelles. A preparation of isolated and purified hphl protein is at least 80% pure; preferably, the preparations are 90%, 95%, or 99% pure. Purity of the preparations may be assessed by any means known in the art, such as SDS-polyacrylamide gel electrophoresis. Polyhomeotic 1 proteins and polypeptides can be produced by recombinant DNA methods or by synthetic chemical methods. For production of recombinant hphl proteins or polypeptides, hphl coding sequences selected from the nucleotide sequence shown in SEQ ID NO:l can be expressed in known prokaryotic or eukaryotic expression systems. Bacterial, yeast, insect, or mammalian expression systems can be used, as is known in the art. Synthetic chemical methods, such as solid phase peptide synthesis, can be used to synthesize hphl protein or polypeptides. Fusion proteins containing at least eight contiguous hphl amino acids can also be constructed. Human polyhomeotic 1 fusion proteins are useful for generating antibodies against hphl amino acid sequences and for use in various assay systems. For example, hphl fusion proteins can be used to identify proteins which interact with hphl protein and influence its function. Physical methods, such as protein affinity chromatography, or library-based assays for protein-protein interactions, such as the yeast two-hybrid or phage display systems, can be used for this puφose. Such methods are well known in the art, and can be used inter alia as drug screens. An hphl fusion protein comprises two protein segments fused together by means of a peptide bond. The first protein segment comprises at least 8, 10, 12, 15, or 20 contiguous amino acids of an hphl protein. The amino acids can be selected from the amino acid sequence shown in SEQ ID NO: 2 or from a naturally or nonnaturally occurring biologically active variant of that sequence. The first protein segment can also be a full-length hphl protein. The second protein segment can be a full-length protein or a protein fragment or polypeptide. The fusion protein can be labeled with a detectable marker, as is known in the art, such as a radioactive, fluorescent, chemiluminescent, or biotinylated marker. The second protein segment can be an enzyme which will generate a detectable product, such as β-galactosidase or other enzymes which are known in the art. Techniques for making fusion proteins, either recombinantly or by covalently linking two protein segments, are also well known. Recombinant DNA methods can be used to construct hphl fusion proteins, for example, by making a DNA construct which comprises hphl coding sequences selected from SEQ ID NO: 1 in proper reading frame with nucleotides encoding the second protein segment and expressing the DNA construct in a host cell, as described below. Isolated and purified hphl proteins, polypeptides, or fusion proteins can be used as immunogens, to obtain a preparation of antibodies which specifically bind to an hphl protein. The antibodies can be used to detect wild-type hphl proteins in human tissue. The antibodies can also be used to detect the presence of mutations in the hphl gene which results in underexpression of the hphl protein or in hphl proteins with altered size or electrophoretic mobilities. Preparations of polyclonal and monoclonal hphl antibodies can be made using standard methods known in the art. The antibodies specifically bind to epitopes present in hphl proteins having the amino acid sequence shown in SEQ ID NO:2. Preferably, the hphl epitopes are not present in other human proteins. Typically, at least 6, 8, 10, or 12 contiguous amino acids are required to form an epitope. However, epitopes which involve non-contiguous amino acids may require more, e.g., at least 15, 25, or 50 amino acids. Antibodies which specifically bind to hphl proteins provide a detection signal at least 5-, 10-, or 20-fold higher than a detection signal provided with other proteins when used in Western blots or other immunochemical assays. Preferably, antibodies which specifically bind hphl proteins do not detect other proteins in immunochemical assays and can immunoprecipitate hphl proteins from solution. Human polyhomeotic 1 antibodies can be purified by methods well known in the art. Preferably, the antibodies are affinity purified, by passing antiserum over a column to which an hphl protein, polypeptide, or fusion protein is bound. The bound antibodies can then be eluted from the column, for example using a buffer with a high salt concentration. Purified and isolated hphl subgenomic polynucleotides can be used, inter alia, as primers to obtain additional copies of the polynucleotides, to express hphl m protein, polypeptides, or fusion proteins, and as probes for identifying wild-type and mutant hphl coding sequences. The probes can also be used to identify the short arm of a human chromosome 12, as described below. Purified and isolated hphl subgenomic polynucleotides of the invention comprise at least 10 contiguous nucleotides selected from SEQ ID NO: 1. Subgenomic hphl polynucleotides according to the invention contain less than a whole chromosome. Preferably, the polynucleotides are intron-free. Subgenomic hphl polynucleotides can be isolated and purified free from other nucleotide sequences using standard nucleic acid purification techniques. For example, restriction enzymes and probes can be used to isolate polynucleotide fragments which comprise the hphl coding sequences. Isolated polynucleotides are in preparations which are free or at least 90% free of other molecules. A number of terms used in the art of genetic engineering and protein chemistry are used herein with the following defined meanings. Two nucleic acid fragments are "homologous" if they are capable of hybridizing to one another under hybridization conditions described in Maniatis et al., op. cit., pp. 320-323. However, by using the following wash conditions-2 x SCC, 0.1% SDS, room temperature twice, 30 minutes each; then 2 x SCC, 0.1% SDS, 50 ° C. once, 30 minutes; then 2 x SCC, room temperature twice, 10 minutes each—homologous sequences can be identified that contain at most about 25-30% basepair mismatches. More preferably, homologous nucleic acid strands contain 15-25% basepair mismatches, even more preferably 5-15% basepair mismatches. These degrees of homology can be selected by using more stringent wash conditions for identification of clones from gene libraries (or other sources of genetic material), as is well known in the art. A DNA fragment is "derived from" an hphl -encoding DNA sequence if it has the same or substantially the same basepair sequence as a region of the coding sequence of the entire hphl molecule. Preferably the DNA sequence has at least 95 % or preferably 98 % or 99 % identity with hphl. Substantially the same means, when referring to biological activities, that the activities are of the same type although they may differ in degree. When referring to amino acid sequences, substantially the same means that the molecules in question have similar biological properties and preferably have at least 85 %, 90 %, or 95 % homology in amino acid sequences. More preferably, the amino acid sequences are at least 98 % identical. In other uses, substantially the same has its ordinary English language meaning. A protein is "derived from" an hphl molecule if it has the same or substantially the same amino acid sequence as a region of the hph 1 molecule. Protein hphl both glycosylated and unglycosylated, or polypeptide derivatives thereof, may be used for producing antibodies, either monoclonal or polyclonal, specific to hphl. By polypeptide derivatives is meant polypeptides differing in length from natural hphl and containing five or more amino acids from hphl in the same primary order as found in hphl as obtained from a natural source. Polypeptide molecules having substantially the same amino acid sequence as Hphl but possessing minor amino acid substitutions that do not substantially affect the ability of the Hphl polypeptide derivatives to interact with Hphl -specific molecules, such as antibodies, are within the definition of Hphl. Derivatives include glycosylated forms, aggregative conjugates with other molecules and covalent conjugates with unrelated chemical moieties. Derivatives also include allelic variants, species variants, and muteins. Truncations or deletions of regions which do not affect biological function are also encompassed. Covalent derivatives are prepared by linkage of functionalities to groups which are found in the amino acid chain or at the N- or C-terminal residue by means known in the art. Hphl -specific molecules include polypeptides such as antibodies that are specific for the Hphl polypeptide containing the naturally occurring Hphl amino acid sequence. By "specific binding polypeptide" is intended polypeptides that bind with Hphl and its derivatives and which have a measurably higher binding affinity for the target polypeptide, i.e., Hphl and polypeptide derivatives of Hphl, than for other polypeptides tested for binding. Higher affinity by a factor of 10 is preferred, more preferably a factor of 100. Binding affinity for antibodies refers to a single binding event (i.e., monovalent binding of an antibody molecule). Specific binding by antibodies also means that binding takes place at the normal binding site of the molecule's antibody (at the end of the arms in the variable region). As discussed above, minor amino acid variations from the natural amino acid sequence of Hphl are contemplated as being encompassed by the term Hphl; in particular, conservative amino acid replacements are contemplated. Conservative replacements are those that take place within a family of amino acids that are related in their side chains. Genetically encoded amino acids are generally divided into four families: (1) acidic=aspartate, glutamate; (2) basic=lysing, arginine, histidine; (3) non-polar=alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan; and (4) uncharged polar=glycine, asparagine, glutamine, cystine, serine, threonine, tyrosine. Phenylalanine, tryptophan, and tyrosine are sometimes classified jointly as aromatic amino acids. For example, it is reasonable to expect that an isolated replacement of a leucine with an isoleucine or valine, an aspartate with a glutamate, a threonine with a serine, or a similar replacement of an amino acid with a structurally related amino acid will not have a major effect on the binding properties of the resulting molecule, especially if the replacement does not involve an amino acid at a binding site involved in an interaction of Hphl . Whether an amino acid change results in a functional peptide can readily be determined by assaying the properties of the Hphl polypeptide derivative. Complementary DNA encoding hphl proteins can be made using reverse transcriptase, with hphl mRNA as a template. The polymerase chain reaction (PCR) can be used to obtain the polynucleotides, using either human genomic DNA or cDNA as a template. Alternatively, synthetic chemistry techniques can be used to synthesize the polynucleotide molecules of the invention. The degeneracy of the genetic code allows alternate nucleotide sequences to be synthesized which will encode a polyhomeotic 1 protein having the amino acid sequence shown in SEQ ID NO:2. All such nucleotide sequences are within the scope of the present invention. An hphl subgenomic polynucleotide of the present invention can be used in an expression construct, to express all or a portion of an hphl protein in a host cell. The host cell comprising the expression construct can be prokaryotic or eukaryotic. A variety of host cells for use in bacterial, yeast, insect, and human expression systems are available and can be used to express the expression construct. The expression constructs can be introduced into the host cells using any technique known in the art. These techniques include transferrin-polycation-mediated DNA transfer, transfection with naked or encapsulated nucleic acids, liposome-mediated cellular fusion, intracellular transportation of DNA-coated latex beads, protoplast fusion, viral infection, electroporation, and calcium phosphate-mediated transfection. The expression construct comprises a promoter which is functional in the particular host cell selected. The skilled artisan can readily select an appropriate promoter from the large number of cell type-specific promoters known and used in the art. The expression construct can also contain a transcription terminator which is functional in the host cell. The expression construct comprises a polynucleotide segment which encodes all or a portion of an hphl protein. The polynucleotide segment is located downstream from the promoter. Transcription of the polynucleotide segment initiates at the promoter. The expression construct can be linear or circular and can contain sequences, if desired, for autonomous replication. The hphl gene maps to human chromosome region 12pl3. Thus, the subgenomic polynucleotides of the invention can be used to identify this chromosome region in metaphase spreads of human chromosomes. Preparations of human metaphase chromosomes can be prepared using standard cytogenetic techniques from human primary tissues or cell lines. Nucleotide probes comprising at least 12 contiguous nucleotides selected from the nucleotide sequence shown in SEQ ID NO: 1 are used to identify the human chromosome. The nucleotide probes can be labeled, for example, with a radioactive, fluorescent, biotinylated, or chemiluminescent label, and detected by well known methods appropriate for the particular label selected. Protocols for hybridizing nucleotide probes to preparations of metaphase chromosomes are well known in the art. A nucleotide probe will hybridize specifically to nucleotide sequences in the chromosome preparations which are complementary to the nucleotide sequence of the probe. A probe which hybridizes specifically to human chromosome region 12pl3 hybridizes to nucleotide sequences present in the hphl gene and not to nucleotide sequences present in other human genes. A probe which hybridizes specifically to an hphl gene provides a detection signal at least 5-, 10-, or 20-fold higher than the background hybridization provided with non-hphl coding sequences. A human chromosome which specifically hybridizes to an hphl nucleotide probe is identified as a human chromosome 12. Preferably, the nucleotide probe identifies the short arm of human chromosome 12. More preferably, the nucleotide probe identifies a pl3 region of human chromosome 12. The present invention also provides a method to identify neoplastic tissue in a human. The expression of an hphl gene can be compared between a first tissue which is suspected of being neoplastic and a second tissue of the human which is normal. The normal tissue can be any tissue of the human, especially those which express the hphl gene including, but not limited to, thymus, testis, heart, prostate, ovary, small intestine, peripheral blood lymphocytes, skeletal muscle, pancreas, lung, liver, and kidney. The tissue suspected of being neoplastic can be derived from a different tissue type of the human, but preferably it is derived from the same tissue type, for example an intestinal polyp or other abnormal growth. A difference between the hphl gene, mRNA, or protein in the two tissues which are compared, for example in molecular weight, amino acid or nucleotide sequence, or relative abundance, indicates a somatic mutation in the hphl gene in the tissue of the human which was suspected of being neoplastic. The hphl genes in the two tissues can be compared by any means known in the art. For example, the two genes can be sequenced, and the sequence of the hphl gene in the tissue suspected of being neoplastic can be compared with the wild-type sequence in the normal tissue. The hphl genes or portions of the hphl genes in the two tissues can be amplified, for example using nucleotide primers selected from the nucleotide sequence shown in SEQ ID NO: 1 in the polymerase chain reaction (PCR). The amplified genes or portions of genes can be hybridized to nucleotide probes selected from the nucleotide sequence shown in SEQ ED NO: 1. The nucleotide probes can be labeled by a variety of methods, such as radiolabeling, biotinylation, or labeling with fluorescent or chemiluminescent tags, and detected by standard methods known in the art. Alternatively, hphl mRNA in the two tissues can be compared. PolyA+ RNA can be isolated from the two tissues as is known in the art. For example, one of skill in the art can readily determine differences in the size or amount of hphl mRNA transcripts between the two tissues that are compared, using Northern blots and nucleotide probes selected from the nucleotide sequence shown in SEQ ID NO:l. Underexpression of hphl mRNA in a tissue sample suspected of being neoplastic compared with the expression of hphl mRNA in a normal tissue is indicative of neoplasia. Any method for analyzing proteins can be used to compare two hphl proteins from matched samples. The sizes of the hphl proteins in the two tissues can be compared, for example, using the antibodies of the present invention to detect hphl proteins in Western blots of protein extracts from the two tissues. Other changes, such as expression levels and subcellular localization, can also be detected immunologically. A lower hphl protein expression level in a tissue suspected of being neoplastic compared with the hphl protein expression level in a normal tissue is indicative of neoplasia. Similarly, comparison of hphl gene sequences or of hphl gene expression products, e.g., mRNA and protein, between a tissue of a human which is suspected of being neoplastic and a normal tissue of a human can be used to diagnose or prognose neoplasia in the human. Such comparisons of hphl genes, mRNA or protein can be made as described above. Underexpression of the hphl gene in the tissue suspected of being neoplastic indicates neoplasia in the tissue. The degree of underexpression of the hphl gene in the neoplastic tissue relative to wild-type expression of the gene in normal tissue, or differences in the amount of underexpression of the hphl gene in the neoplastic tissue over time, can be used to prognose the progression of the neoplasia in that tissue or to monitor the response of the neoplastic tissue to various therapeutic regimens over time. In addition, a genetic predisposition to neoplasia in a human can be detected by comparing a wild-type hphl gene, mRNA, or protein with an hphl gene, mRNA or protein in a fetal tissue. Fetal tissues which can be used for this puφose include, but are not limited to, amniotic fluid, chorionic villi, blood, and the blastomere of an in v/tro-fertilized embryo. The wild-type hphl gene can be obtained from any tissue. The mRNA or protein can be obtained from a normal tissue of a human in which the hphl gene is expressed. Such tissues are disclosed above. Differences such as alterations in the nucleotide sequence or size of the fetal hphl gene or mRNA, or alterations in the molecular weight, amino acid sequence, or relative abundance of fetal hphl protein indicate a germline mutation in the hphl gene of the fetus which indicates a genetic predisposition to neoplasia. The invention provides a therapeutic composition for restoring a wild-type hphl function to a cell which has lost that function. Wild-type hphl functions include suppression of neoplasia and of dysplastic or hypeφlastic cell growth, as well as the ability to induce cellular differentiation. The cell can be any cell of a human which would normally express the wild-type hphl gene, such as thymus, testis, heart, prostate, ovary, small intestine, peripheral blood lymphocytes, skeletal muscle, pancreas, lung, liver, and kidney, but which lacks hphl expression or expresses an altered form of hphl mRNA or protein. Such cells include neoplasias of the tissues mentioned above as well as any other neoplastic cells which have lost wild-type polyhomeotic 1 function. The therapeutic composition comprises all or a portion of a wild-type human hphl gene or gene expression product in a pharmaceutically acceptable carrier. The hphl expression product can be, e.g., mRNA or protein. A portion of a wild-type hphl gene, mRNA or protein can also be used if it is capable of restoring wild-type hphl function to the cell. Pharmaceutically acceptable carriers are well known to those in the art. Such carriers include, but are not limited to, large, slowly metabolized macromolecules such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, amino acid copolymers, and inactive virus particles. Pharmaceutically acceptable salts can also be used in the composition, for example, mineral salts such as hydrochlorides, hydrobromides, phosphates, or sulfates, as well as the salts of organic acids such as acetates, proprionates, malonates, or benzoates. The composition can also contain liquids, such as water, saline, glycerol, and ethanol, as well as substances such as wetting agents, emulsifying agents, or pH buffering agents. Liposomes, such as those described in U.S. 5,422,120, WO 95/13796, WO 91/14445, or EP 524,968 Bl, can also be used as a carrier for the therapeutic polyhomeotic 1 composition. Typically, the therapeutic hphl composition is prepared as an injectable, either as a liquid solution or suspension, however solid forms suitable for solution in, or suspension in, liquid vehicles prior to injection can also be prepared. The composition can also be formulated into an enteric coated tablet or gel capsule according to known methods in the art, such as those described in U.S. 4,853,230, EP 225,189, AU 9,224,296, and AU 9,230,801. Proliferative disorders, such as neoplasias, dysplasias, and hypeφlasias, can be treated by administration of the therapeutic hphl composition. Neoplasias which can be treated with the therapeutic composition include, but are not limited to, melanomas, squamous cell carcinomas, adenocarcinomas, hepatocellular carcinomas, renal cell carcinomas, sarcomas, myosarcomas, non-small cell lung carcinomas, leukemias, lymphomas, osteosarcomas, central nervous system tumors such as gliomas, astrocytomas, oligodendrogliomas, and neuroblastomas, tumors of mixed origin, such as Wilms * tumor and teratocarcinomas, and metastatic tumors. Proliferative disorders which can be treated with the therapeutic composition include disorders such as anhydric hereditary ectodermal dysplasia, congenital alveolar dysplasia, epithelial dysplasia of the cervix, fibrous dysplasia of bone, and mammary dysplasia. Hypeφlasias, for example, endometrial, adrenal, breast, prostate, or thyroid hypeφlasias or pseudoepitheliomatous hypeφlasia of the skin can be treated with wild- type hphl therapeutic compositions. Even in disorders in which hphl mutations are not implicated, upregulation or enhancement of hphl function can have therapeutic application. In these disorders, increasing hphl expression or enhancing hphl function can help to suppress tumors. Similarly, in tumors where hphl expression is not aberrant, effecting hphl upregulation or augmentation of hphl activity can suppress metastases. Both the dose of ' the hphl composition and the means of administration can be determined based on the specific qualities of the therapeutic composition, the condition, age, and weight of the patient, the progression of the disease, and other relevant factors. If the composition contains hphl protein or polypeptide, effective dosages of the composition are in the range of about 5 μg to about 50 μg/kg of patient body weight, also about 50 μg to about 5 mg/kg, also about 100 μg to about 500 μg/kg of patient body weight, and about 200 to about 250 μg/kg. Administration of the therapeutic agents of the invention can include local or systemic administration, including injection, oral administration, particle gun or catheterized administration, and topical administration. Alternatively, the therapeutic composition can contain hphl polynucleotides. Preferably, the therapeutic composition contains an expression construct comprising a promoter and a polynucleotide segment encoding at least eight contiguous amino acids of hphl protein. Within the expression construct, the polynucleotide segment is located downstream from the promoter, and transcription of the polynucleotide segment initiates at the promoter. Various methods can be used to administer the therapeutic composition directly to a specific site in the body. For example, a small metastatic lesion can be located and the therapeutic composition injected several times in several different locations within the body of tumor. Alternatively, arteries which serve a tumor can be identified, and the therapeutic composition injected into such an artery, in order to deliver the composition directly into the tumor. A tumor which has a necrotic center an be aspirated and the composition injected directly into the now empty center of the tumor. The hphl composition can be directly administered to the surface of the tumor, for example, by topical application of the composition. X-ray imaging can be used to assist in certain of the above delivery methods. Additionally, combination therapeutic agents including an hphl protein or polypeptide or a subgenomic hphl polynucleotide and other therapeutic agents can be administered together. The co-administration can be simultaneous, achieved for example by placing polynucleotides encoding the agents in the same expression construct, or by putting the agents, whether polynucleotide, polypeptide, or other drug, in the same pharmaceutical composition, or by administering the agents in different phaπnaceutical compositions injected at about the same time in the same location. If the co-administration is not simultaneous, for example, in the case of administration of a prodrug after administration of a prodrug activator, the second agent can be administered by direct injection as appropriate for the goals of the therapy. Thus, for example, in the case of an administration of a prodrug, the prodrug is administered at the same location as the prodrug activator. Thus, a co-administration protocol can include a combination of administrations to achieve the goal of the therapy. The co- administration can include subsequent administrations as is necessary. Receptor-mediated targeted delivery of therapeutic compositions containing hphl subgenomic polynucleotides to specific tissues can also be used. Receptor- mediated DNA delivery techniques are described in, for example, Findeis et al. (1993), Trends in Biotechnol. 11, 202-05; Chiou et al. (1994), GENE THERAPEUTICS: METHODS ANDAPPUCAΗONS OF DIRECT GENE TRANSFER (J.A. Wolff, ed.); Wu & Wu (1988), J. Biol. Chem. 263, 621-24; Wu et al. (1994), J. Biol. Chem. 269, 542-46; Zenke et al. (1990), Proc. Natl. Acad Sci. U.S.A. 87, 3655-59; Wu et al. (1991), J. Biol. Chem. 266, 338-42. Alternatively, the composition containing subgenomic hphl polynucleotides can be introduced into human cells ex vivo and then replaced into the human. Cells can be removed from a variety of locations including, for example, from a selected tumor or from an affected organ. In addition, the therapeutic composition can be inserted into non-tumorigenic cells, for example, dermal fibroblasts or peripheral blood leukocytes. If desired, particular fractions of cells such as a T cell subset or stem cells can also be specifically removed from the blood (see, for example, PCT WO 91/16116). The A ?A7-containing therapeutic composition can then be contacted with the removed cells utilizing any of the above-described techniques, followed by the return of the cells to the human, preferably to or within the vicinity of a tumor. The above-described methods can additionally comprise the steps of depleting fibroblasts or other non- contaminating tumor cells subsequent to removing tumor cells from a human, and/or the step of inactivating the cells, for example, by irradiation. Therapeutic compositions containing hphl subgenomic polynucleotides can be administered in a range of about 100 ng to about 200 mg of DNA for local administration in a gene therapy protocol. Concentration ranges of about 500 ng to about 50 mg, about 1 μg to about 2 mg, about 5 μg to about 500 μg, and about 20 μg to about 100 μg of DNA can also be used during a gene therapy protocol. Factors such as method of action and efficacy of transformation and expression are considerations that will effect the dosage required for ultimate efficacy of the hphl subgenomic polynucleotides. Where greater expression is desired over a larger area of tissue, larger amounts of hphl subgenomic polynucleotides or the same amounts readministered in a successive protocol of administrations, or several administrations to different adjacent or close tissue portions of for example, a tumor site, may be required to effect a positive therapeutic outcome. In all cases, routine experimentation in clinical trials will determine specific ranges for optimal therapeutic effect. The hphl therapeutic composition can also be used to induce differentiation of a progenitor cell, e.g., in order to study the process of differentiation and test compounds which affect this process. Induction of differentiation is also desirable, for example, in the treatment of anaplastic tumors, which are composed of cells which have lost some of their differentiated characteristics. Progenitor cells which can be induced to differentiate using an hphl therapeutic composition comprising hphl subgenomic polynucleotides, proteins, polypeptides, or fusion proteins include, but are not limited to, erythropoietic stem cells, neuroblasts, chrondroblasts, melanoblasts, myoblasts, and neural crest cells. In addition to methods using the hphl therapeutic composition described above, expression of an endogenous hphl gene in a cell can be altered by introducing in frame with the endogenous hphl gene a DNA construct comprising an hphl targeting sequence, a regulatory sequence, an exon, and an unpaired splice donor site by homologous recombination, such that a homologously recombinant cell comprising the DNA construct is formed. This method of affecting endogenous gene expression is taught in U.S. Patent No. 5,641,670, which is incoφorated herein in its entirety by reference. The targeting sequence is selected from the nucleotide sequence shown in SEQ ID NO:l. The transcription unit is located upstream of a coding sequence of the endogenous hphl gene. The exogenous regulatory sequence directs transcription of the coding sequence of the hphl gene. Preferably, the homologously recombinant cell is a progenitor cell or a neoplastic cell, and the exogenous regulatory sequence directs enhanced transcription of the coding sequence of the hphl gene. Cells transformed with wild-type hphl subgenomic polynucleotides can be used as model systems to study cancer remission and drug treatments which promote such remission. Suppression of the neoplastic phenotype is a process which involves alterations in gene expression in the transformed cells. These alterations in gene expression will be reflected in moφhological and biochemical changes in the transformed cells. Moφhological changes can be studied, for example, by observing the transformed cells microscopically and comparing the appearance of the transformed cells with cells which have not received a wild-type hphl gene. Biochemical alterations can be studied, inter alia, by comparing the proteins which are expressed by the cells before and at various times after transformation with the wild-type hphl gene. Methods of comparing proteins between two cells, such as using SDS polyacrylamide electrophoresis, are well known in the art. Cells transformed with a wild-type hphl gene and in the process of suppressing neoplastic growth can also be exposed to various drug treatments to determine which treatments promote the moφhological or biochemical changes which accompany suppression of the neoplastic phenotype. Similarly, cells transformed with wild-type hphl subgenomic polynucleotides can also be used to study the changes which accompany cellular differentiation in progenitor cells and the response of these cells to test compounds which affect differentiation. A more complete description of gene therapy vectors, especially retroviral vectors is contained in U.S. Serial No. 08/869,309, which is expressly incoφorated herein. SYNOPSIS OF THE INVENTION 1. An isolated and purified human polyhomeotic 1 protein having the amino acid sequence shown in SEQ ID NO:2. 2. An isolated and purified human polyhomeotic 1 polypeptide consisting of at least 22 contiguous amino acids selected from the amino acid sequence shown in SEQ ID NO:2. 3. An hphl fusion protein comprising a first protein segment and a second protein segment fused together by means of a peptide bond, wherein the first protein segment consists of at least 8 contiguous amino acids of a human polyhomeotic 1 protein. 4. A preparation of antibodies which specifically bind to a human polyhomeotic 1 protein. 5. The preparation of antibodies of item 4 wherein the antibodies are monoclonal. 6. The preparation of antibodies of item 4 wherein the antibodies are polyclonal. 7. An isolated and purified subgenomic polynucleotide consisting of at least 10 contiguous nucieotides selected from the nucleotide sequence shown in SEQ IO NO: l. 8. An expression construct for expressing all or a portion of a human polyhomeotic 1 protein comprising: a promoter; and a polynucleotide segment encoding at least 8 contiguous amino acids of a human polyhomeotic 1 protein, wherein the polynucleotide segment is located downstream from the promoter, wherein transcription of the polynucleotide segment initiates at the promoter. 9. A host cell comprising the expression construct of item 8. 10. A homologously recombinant cell having incoφorated therein a new transcription initiation unit, wherein the new transcription inititation unit comprises: (a) an exogenous regulatory sequence; (b) an exogenous exon; and (c) a splice donor site, wherein the transcription initiation unit is located upstream of a coding sequence of an hphl gene, wherein the exogenous regulatory sequence directs transcription of the coding sequence of the hphl gene. 11. The homologously recombinant cell of item 10 wherein the exogenous regulatory sequence directs enhanced transcription of the coding sequence of the hphl gene. 12. The homologously recombinant cell of item 10 wherein the homologously recombinant cell is a neoplastic cell. 13. The homologously recombinant cell of item 10 wherein the homologously recombinant cell is a progenitor cell. 14. A method of identifying neoplastic tissue of a human, comprising: comparing the expression of a polyhomeotic 1 gene in a first tissue of a human suspected of being neoplastic with the expression of a polyhomeotic 1 gene in a second tissue of the human which is normal, wherein underexpression of the human polyhomeotic 1 gene in the first tissue identifies the first tissue as being neoplastic. 15. The method of item 14 wherein the polyhomeotic 1 genes in the first and second tissues are compared by sequencing the polyhomeotic 1 genes in the first and second tissues. 16. The method of item 14 wherein the difference in the polyhomeotic 1 gene between the first and second tissues is detected by amplification of the polyhomeotic 1 genes of the first and second tissues and hybridization of the amplified genes to nucleotide probes. 17. The method of item 14 wherein polyhomeotic 1 mRNA is compared between the first and second tissues. 18. The method of item 14 wherein a polyhomeotic 1 protein is compared between the first and second tissues. 19. A method to aid in the diagnosis or prognosis of neoplasia in a human, comprising: comparing a polyhomeotic 1 gene, mRNA or protein in a first tissue of a human suspected of being neoplastic with a polyhomeotic 1 gene, mRNA, or protein in a second tissue of a human which is normal, wherein a difference between the polyhomeotic 1 genes, mRNAs, or proteins in the first and second tissues indicates neoplasia in the first tissue. 20. The method of item 19 wherein the polyhomeotic 1 genes in the first and second tissues are compared by sequencing the polyhomeotic 1 genes in the first and second tissues. 21. The method of item 19 wherein the difference in the polyhomeotic 1 gene between the first and second tissues is detected by amplification of the polyhomeotic 1 genes of the first and second tissues and hybridization of the amplified genes to nucleotide probes. 22. The method of item 19 wherein polyhomeotic mRNA is compared. 23. The method of item 19 wherein polyhomeotic protein is compared. 24. A method to aid in detecting a genetic predisposition to neoplasia in a human, comprising: comparing a polyhomeotic 1 gene, mRNA or protein in the fetal tissue of a human with a wild-type human polyhomeotic 1 gene, mRNA, or protein, wherein a difference between the polyhomeotic 1 gene, mRNA, or protein in the fetal tissue of the human and the wild-type human polyhomeotic 1 gene, mRNA, or protein indicates a genetic predisposition to neoplasia in the human. 25. The method of item 24 wherein a polyhomeotic 1 mRNA is compared. 26. The method of item 24 wherein a polyhomeotic 1 gene is compared. 27. The method of item 24 wherein the difference between the polyhomeotic 1 genes is detected by amplification of the wild-type human polyhomeotic 1 gene and the human polyhomeotic 1 gene in the fetal tissue and hybridizing the amplified genes to nucleotide probes. 28. The method of item 24 wherein a human polyhomeotic 1 protein is compared. 29. A method of identifying a human chromosome 12, comprising the steps of: contacting a preparation of metaphase human chromosomes with a nucleotide probe comprising at least 12 contiguous nucieotides selected from the nucleotide sequence shown in SEQ ID NO: 1; and detecting a region of a chromosome which specifically hybridizes to the nucleotide probe, wherein a region of a chromosome which specifically hybridizes to the nucleotide probe is identified as a human chromosome 12. 30. The method of item 29 wherein the region of the chromosome which specifically hybridizes to the nucleotide probe is identified as the short arm of a human chromosome 12. 31. The method of item 29 wherein the region of the chromosome which specifically hybridizes to the nucleotide probe is identified as a pl3 region of a human chromosome 12. 32. A therapeutic composition for restoring a wild-type human polyhomeotic 1 function to a cell which lacks that function, comprising: all or a portion of a wild-type human polyhomeotic 1 gene or expression product, wherein said all or a portion of the wild-type human polyhomeotic 1 gene or expression product is capable of restoring a wild-type polyhomeotic 1 function to a cell; and a pharmaceutically acceptable carrier. 33. A method of treating proliferative disorders, comprising the step of administering to a human a composition comprising all or a portion of a wild-type human polyhomeotic 1 gene or expression product, wherein said all or a portion of the wild-type human polyhomeotic 1 gene or expression is capable of restoring or enhancing a wild-type polyhomeotic 1 function to a cell. 34. A method of inducing a cell to differentiate, comprising the step of contacting a progenitor cell with a composition comprising all or a portion of a human polyhomeotic 1 gene or expression product, wherein said all or a portion of the human polyhomeotic 1 gene or expression product is capable of inducing differentiation of the cell. SEQUENCE LISTING (1) GENERAL INFORMATION: (I) APPLICANT: RANDAZZO, FILIPPO (ii) TITLE OF INVENTION: HUMAN POLYHOMEOTIC 1 (hphl) ACTS AS A TUMOR SUPPRESSOR (iii) NUMBER OF SEQUENCES: 2 (iv) CORRESPONDENCE ADDRESS: (A) ADDRESSEE: CHIRON CORPORATION (B) STREET: 4560 HORTON STREET (C) CITY: EMERYVILLE (D) STATE: CA (E) COUNTRY: USA (F) ZIP: 94608 (v) COMPUTER READABLE FORM: (A) MEDIUM TYPE: Floppy disk (B) COMPUTER: IBM PC compatible (C) OPERATING SYSTEM: PC-DOS/MS-DOS (D) SOFTWARE: Patentln Release #1.0, Version #1.30 (vi) CURRENT APPLICATION DATA: (A) APPLICATION NUMBER: (B) FILING DATE: (C) CLASSIFICATION: (viii) ATTORNEY/AGENT INFORMATION: (A) NAME: POTTERFIRESTONE, LEIGH H. (B) REGISTRATION NUMBER: 36,831 (C) REFERENCE/DOCKET NUMBER: 1355. (ix) TELECOMMUNICATION INFORMATION: (A) TELEPHONE: 510-923-2707 (B) TELEFAX: 510-655-3542 (2) INFORMATION FOR SEQ ID NO:l: (I) SEQUENCE CHARACTERISTICS: (A) LENGTH: 3879 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:l: ATGGAGACTG AGAGCGAGCA GAACTCCAAT TCCACCAATG GGAGTTCTAG CTCAGGGGGC 60 AGCTCTCGGC CCCAGATAGC TCAAATGTCA CTATATGAAC GACAAGCAGT GCAGGCTCTG 120 CAAGCACTGC AGCGGCAGCC CAATGCAGCT CAGTATTTCC ACCAGTTCAT GCTCCAGCAG 180 CAGCTCAGTA ATGCCCAGCT GCATAGCCTG GCTGCCGTCC AGCAGGCCAC AATTGCTGCC 240 AGTCGGCAGG CCAGCTCCCC AAACACCAGC ACTACACAGC AGCAGACTAC CACCACCCAG 300 GCCTCGATCA ATCTGGCCAC CACATCGGCC GCCCAGCTCA TCAGCCGATC CCAGAGTGTG 360 AGCTCTCCTA GTGCTACCAC CTTGACCCAA TCTGTGCTAC TGGGGAACAC CACCTCCCCA 420 CCCCTCAACC AGTCTCAGGC CCAGATGTAT CTACGGCCAC AGCTGGGAAA CCTATTGCAG 480 GTAAACCGAA CCCTGGGTCG GAATGTGCCT CTAGCCTCCC AACTCATCCT GATGCCTAAT 540 GGGGCGGTGG CTGCAGTCCA GCAGGAGGTG CCATCTGCTC AGTCTCCTGG AGTTCATGCA 600 GATGCAGATC AGGTTCAGAA CTTGGCAGTA AGGAATCAAC AGGCCTCAGC TCAAGGACCT 660 CAGATGCAAG GCTCCACTCA GAAGGCCATT CCTCCAGGAG CCTCCCCTGT CTCTAGCCTC 720 TCCCAGGCCT CTAGCCAGGC CCTAGCGGTG GCACAGGCTT CCTCTGGGGC CACAAACCAG 780 TCCCTCAACC TTAGTCAAGC TGGTGGAGGC AGTGGGAATA GCATCCCAGG GTCCATGGGT 840 CCAGGTGGAG GTGGGCAGGC ACATGGTGGT TTGGGTCAGT TGCCTTCCTC AGGAATGGGT 900 GGTGGGAGCT GTCCCAGGAA GGGTACAGGA GTGGTGCAGC CCTTGCCTGC AGCCCAAACA 960 GTGACTGTGA GCCAGGGCAG CCAGACAGAG GCAGAAAGTG CAGCAGCCAA GAAGGCAGAA 1020 GCAGATGGGA GTGGCCAGCA GAATGTGGGC ATGAACCTGA CACGGACAGC CACACCTGCG 1080 CCCAGCCAGA CACTTATTAG CTCAGCCACC TACACACAGA TCCAGCCCCA TTCACTGATT 1140 CAGCAACAGC AACAGATCCA CCTCCAGCAG AAACAGGTGG TGATCCAGCA GCAGATTGCC 1200 ATCCACCACC AGCAGCAGTT CCAGCACCGG CAGTCCCAGC TCCTTCACAC AGCTACACAC 1260 CTCCAGTTGG CGCAGCAGCA GCAGCAGCAA CAACAGCAAC AGCAGCAACA GCAGCAGCCG 1320 CAAGCCACCA CCCTCACTGC CCCTCAGCCA CCACAGGTCC CACCTACTCA GCAGGTCCCA 1380 CCTTCCCAGT CCCAGCAGCA AGCCCAAACC CTGGTCGTTC AGCCCATGCT TCAGTCTTCA 1440 CCCTTGTCTC TTCCACCTGA TGCAGCCCCT AAGCCACCAA TTCCCATCCA ATCCAAACCA 1500 CCTGTAGCAC CTATCAAGCC GCCTCAGTTA GGGGCCGCTA AGATGTCAGC TGCCCAGCAA 1560 CCACCACCCC ATATCCCTGT GCAAGTTGTA GGCACTCGAC AGCCAGGTAC AGCCCAGGCA 1620 CAGGCTTTGG GGTTGGCACA GCTGGCAGCT GCTGTACCTA CTTCCCGGGG GATGCCAGGT 1680 ACAGTGCAGT CTGGTCAGGC CCATTTGGCC TCCTCGCCAC CTTCATCCCA GGCTCCTGGT 1740 GCACTGCAGG AGTGCCCTCC CACATTGGCC CCTGGGATGA CCCTTGCTCC TGTGCAGGGG 1800 ACAGCACATG TGGTAAAGGG TGGGGCTACC ACCTCCTCAC CTGTTGTAGC CCAGGTCCCT 1860 GCTGCCTTCT ATATGCAGTC TGTGCACTTG CCGGGTAAAC CCCAGACATT GGCTGTCAAA 1920 CGCAAGGCTG ACTCTGAGGA GGAGAGAGAT GATGTCTCCA CATTGGGTTC AATGCTTCCT 1980 GCCAAAGCAT CTCCAGTAGC AGAAAGCCCA AAAGTCATGG ACGAGAAGAG CAGTCTTGGA 2040 GAAAAAGCTG AATCAGTGGC TAATGTGAAT GCTAATACTC CAAGCAGTGA ACTAGTAGCC 2100 TTGACCCCCG CCCCTTCAGT ACCGCCTCCT ACACTAGCCA TGGTGTCTAG ACAAATGGGT 2160 GACTCAAAAC CCCCACAGGC CATCGTGAAG CCCCAGATTC TCACCCACAT CATTGAAGGC 2220 TTTGTTATCC AGGAAGGAGC AGAACCTTTC CCGGTGGGTT GTTCTCAGTT ACTGAAGGAG 2280 TCTGAGAAGC CACTACAGAC TGGCCTTCCG ACAGGGCTGA CTGAGAATCA GTCAGGTGGC 2340 CCTTTGGGAG TGGACAGCCC ATCTGCTGAG TTAGATAAGA AGGCGAATCT CCTGAAGTGC 2400 GAGTACTGTG GGAAGTACGC CCCCGCAGAG CAGTTTCGTG GCTCTAAGAG GTTCTGCTCC 2460 ATGACTTGCG CTAAGAGGTA CAATGTGAGC TGTAGCCATC AGTTCCGGCT GAAGAGGAAA 2520 AAAATGAAAG AGTTTCAAGA AGCCAACTAT GCTCGCGTTC GCAGGCGTGG ACCCCGCCGC 2580 AGCTCCTCTG ACATTGCCCG TGCCAAGATT CAGGGCAAGT GCCACCGGGG TCAAGAAGAC 2640 TCTAGCCGGG GTTCAGATAA TTCCAGTTAT GATGAAGCAC TCTCTCCAAC ATCTCCTGGG 2700 CCTTTATCAG TAAGAGCTGG GCATGGAGAA CGTGACCTGG GGAATCCCAA TACAGCTCCA 2760 CCTACACCGG AATTACATGG CATCAACCCT GTGTTCCTGT CCAGTAATCC CAGCCGTTGG 2820 AGTGTAGAGG AGGTGTACGA GTTTATTGCT TCTCTCCAAG GCTGCCAAGA GATTGCAGAG 2880 GAATTTCGCT CACAGGAGAT TGATGGACAG GCCCTTTTAT TACTTAAAGA AGAACATCTT 2940 ATGAGTGCCA TGAACATCAA GCTGGGCCCT GCCCTCAAGA TCTGCGCCAA GATAAATGTC 3000 CTCAAGGAGA CCTAAGGTGG CCCTCTTGCA CAAACCAGCC TAAGGCAGAC ACTCTCCACT 3060 GTCCAGGTTA TAACCTGGTA CCAGCAGACT TTGCAGGGAA GAAAGAGTTG TTCCAATCAT 3120 GTAACCTTCT GTAGGGGATT ACTGAGACAG GGAAGAGAAG TGCAAGAATT GGTTGCTGGT 3180 GCTACATGGC GGCAGCTTTG ACATTTTCTC TGGGTTCTAC TTTATTTTTT AAAATCTTTA 3240 CAGTTCTCAC CATTTCACGT ACCTTAATCC AATCTTTATA AAAGAGGCAG TCTAGAGAAC 3300 TAGGACTGCT CAGCCTTATC CTGGAGTGGA GCATTTAGCC CAGGTCTTAA TTCTCCAAGA 3360 GGAGGAATAC ATAGTATGGT AAGGCAAGGA ACTGGGTGGA ATGTCAGGTT GCCTGCCCAA 3420 TGGGAGAGGT AGGGTTTTTC TAGCTTGTGT GACAGAAGTA GCAAAATCTG GTCCTCCCCC 3480 CTCCCAGTGT AGCTGTGGCT CAGAGTTTTT TCTTTTTGTT GTCACTTACT CCCTTGTGAT 3540 TGAATTTTTT CTCCTGCATC CATGGCAGGA TCCCCAGCCA GTATAGAGAC TTGGTTGGCA 3600 TCTTCTGCTG CAGGGACTAA AAGTATTTGA CTGGGGCACA TGTGGCTGTT GTCATTCTTT 3660 CTGCATCCCA CTGTTCCCCT CCAATTTATG TTATTTTCTA CCCTGTTTTT CAGTTCCATC 3720 TCTGCTCTGT CCTATAGCTT TATAAAACCA GAGTGTGTGG GGCTGAGGTC AGGAGTATAA 3780 GTACCTGCCT TAGGCACTAT TCCTTATATA ACAAAAATAT TAAATATTTT TTTCCTCAGT 3840 AAAAGGATGA AAATTGGTAA AAAAAAAAAA AAAAAAAGG 3879 (2) INFORMATION FOR SEQ ID NO: 2: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1004 amino acids (B) TYPE: amino acid (C) STRANDEDNESS : single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 2: Met Glu Thr Glu Ser Glu Gin Asn Ser Asn Ser Thr Asn Gly Ser Ser 1 5 10 15 Ser Ser Gly Gly Ser Ser Arg Pro Gin He Ala Gin Met Ser Leu Tyr 20 25 30 Glu Arg Gin Ala Val Gin Ala Leu Gin Ala Leu Gin Arg Gin Pro Asn 35 40 45 Ala Ala Gin Tyr Phe His Gin Phe Met Leu Gin Gin Gin Leu Ser Asn 50 55 60 Ala Gin Leu Hie Ser Leu Ala Ala Val Gin Gin Ala Thr He Ala Ala 65 70 75 80 Ser Arg Gin Ala Ser Ser Pro Asn Thr Ser Thr Thr Gin Gin Gin Thr 85 90 95 Thr Thr Thr Gin Ala Ser He Asn Leu Ala Thr Thr Ser Ala Ala Gin 100 105 110 Leu He Ser Arg Ser Gin Ser Val Ser Ser Pro Ser Ala Thr Thr Leu 115 120 125 Thr Gin Ser Val Leu Leu Gly Asn Thr Thr Ser Pro Pro Leu Asn Gin 130 135 140 Ser Gin Ala Gin Met Tyr Leu Arg Pro Gin Leu Gly Asn Leu Leu Gin 145 150 155 160 Val Asn Arg Thr Leu Gly Arg Asn Val Pro Leu Ala Ser Gin Leu He 165 170 175 Leu Met Pro Asn Gly Ala Val Ala Ala Val Gin Gin Glu Val Pro Ser 180 185 190 Ala Gin Ser Pro Gly Val His Ala Asp Ala Asp Gin Val Gin Asn Leu 195 200 205 Ala Val Arg Asn Gin Gin Ala Ser Ala Gin Gly Pro Gin Met Gin Gly 210 215 220 Ser Thr Gin Lys Ala He Pro Pro Gly Ala Ser Pro Val Ser Ser Leu 225 230 235 240 Ser Gin Ala Ser Ser Gin Ala Leu Ala Val Ala Gin Ala Ser Ser Gly 245 250 255 Ala Thr Asn Gin Ser Leu Asn Leu Ser Gin Ala Gly Gly Gly Ser Gly 260 265 270 Asn Ser He Pro Gly Ser Met Gly Pro Gly Gly Gly Gly Gin Ala His 275 280 285 Gly Gly Leu Gly Gin Leu Pro Ser Ser Gly Met Gly Gly Gly Ser Cys 290 295 300 Pro Arg Lys Gly Thr Gly Val Val Gin Pro Leu Pro Ala Ala Gin Thr 305 310 315 320 Val Thr Val Ser Gin Gly Ser Gin Thr Glu Ala Glu Ser Ala Ala Ala 325 330 335 Lys Lys Ala Glu Ala Asp Gly Ser Gly Gin Gin Asn Val Gly Met Asn 340 345 350 Leu Thr Arg Thr Ala Thr Pro Ala Pro Ser Gin Thr Leu He Ser Ser 355 360 365 Ala Thr Tyr Thr Gin He Gin Pro His Ser Leu He Gin Gin Gin Gin 370 375 380 Gin He His Leu Gin Gin Lys Gin Val Val He Gin Gin Gin He Ala 385 390 395 400 He His His Gin Gin Gin Phe Gin His Arg Gin Ser Gin Leu Leu His 405 410 415 Thr Ala Thr His Leu Gin Leu Ala Gin Gin Gin Gin Gin Gin Gin Gin 420 425 430 Gin Gin Gin Gin Gin Gin Gin Pro Gin Ala Thr Thr Leu Thr Ala Pro 435 440 445 Gin Pro Pro Gin Val Pro Pro Thr Gin Gin Val Pro Pro Ser Gin Ser 450 455 460 Gin Gin Gin Ala Gin Thr Leu Val Val Gin Pro Met Leu Gin Ser Ser 465 470 475 480 Pro Leu Ser Leu Pro Pro Asp Ala Ala Pro Lys Pro Pro He Pro He 485 490 495 Gin Ser Lys Pro Pro Val Ala Pro He Lys Pro Pro Gin Leu Gly Ala 500 505 510 Ala Lye Met Ser Ala Ala Gin Gin Pro Pro Pro His He Pro Val Gin 515 520 525 Val Val Gly Thr Arg Gin Pro Gly Thr Ala Gin Ala Gin Ala Leu Gly 530 535 540 Leu Ala Gin Leu Ala Ala Ala Val Pro Thr Ser Arg Gly Met Pro Gly 545 550 555 560 Thr Val Gin Ser Gly Gin Ala Hie Leu Ala Ser Ser Pro Pro Ser Ser 565 570 575 Gin Ala Pro Gly Ala Leu Gin Glu Cys Pro Pro Thr Leu Ala Pro Gly 580 565 590 Met Thr Leu Ala Pro Val Gin Gly Thr Ala His Val Val Lys Gly Gly 595 600 605 Ala Thr Thr Ser Ser Pro Val Val Ala Gin Val Pro Ala Ala Phe Tyr 610 615 620 Met Gin Ser Val His Leu Pro Gly Lys Pro Gin Thr Leu Ala Val Lys 625 630 635 640 Arg Lys Ala Asp Ser Glu Glu Glu Arg Asp Asp Val Ser Thr Leu Gly 645 650 655 Ser Met Leu Pro Ala Lys Ala Ser Pro Val Ala Glu Ser Pro Lys Val 660 665 670 Met Asp Glu Lys Ser Ser Leu Gly Glu Lys Ala Glu Ser Val Ala Asn 675 680 685 Val Asn Ala Asn Thr Pro Ser Ser Glu Leu Val Ala Leu Thr Pro Ala 690 695 700 Pro Ser Val Pro Pro Pro Thr Leu Ala Met Val Ser Arg Gin Met Gly 705 710 715 720 Asp Ser Lys Pro Pro Gin Ala He Val Lys Pro Gin He Leu Thr His 725 730 735 He He Glu Gly Phe Val He Gin Glu Gly Ala Glu Pro Phe Pro Val 740 745 750 Gly Cyβ Ser Gin Leu Leu Lys Glu Ser Glu Lys Pro Leu Gin Thr Gly 755 760 765 Leu Pro Thr Gly Leu Thr Glu Asn Gin Ser Gly Gly Pro Leu Gly Val 770 775 780 Asp Ser Pro Ser Ala Glu Leu Asp Lys Lys Ala Asn Leu Leu Lys Cys 785 790 795 800 Glu Tyr Cys Gly Lys Tyr Ala Pro Ala Glu Gin Phe Arg Gly Ser Lys 805 810 815 Arg Phe Cyβ Ser Met Thr Cys Ala Lys Arg Tyr Asn Val Ser Cys Ser 820 825 830 His Gin Phe Arg Leu Lye Arg Lys Lys Met Lys Glu Phe Gin Glu Ala 835 840 845 Asn Tyr Ala Arg Val Arg Arg Arg Gly Pro Arg Arg Ser Ser Ser Asp 850 855 860 He Ala Arg Ala Lye He Gin Gly Lys Cys His Arg Gly Gin Glu Asp 865 870 875 880 Ser Ser Arg Gly Ser Asp Asn Ser Ser Tyr Asp Glu Ala Leu Ser Pro 885 890 895 Thr Ser Pro Gly Pro Leu Ser Val Arg Ala Gly His Gly Glu Arg Asp 900 905 910 Leu Gly Asn Pro Asn Thr Ala Pro Pro Thr Pro Glu Leu His Gly He 915 920 925 Aan Pro Val Phe Leu Ser Ser Asn Pro Ser Arg Trp Ser Val Glu Glu 930 935 940 Val Tyr Glu Phe He Ala Ser Leu Gin Gly Cys Gin Glu He Ala Glu 945 950 955 960 Glu Phe Arg Ser Gin Glu He Asp Gly Gin Ala Leu Leu Leu Leu Lys 965 970 975 Glu Glu Hie Leu Met Ser Ala Met Asn He Lys Leu Gly Pro Ala Leu 980 985 990 Lye He Cys Ala Lys He Asn Val Leu Lys Glu Thr 995 1000

Claims: CLAIMS 1. An isolated and purified human polyhomeotic 1 protein having the amino acid sequence shown in SEQ ID NO:2. 2. An isolated and purified human polyhomeotic 1 polypeptide consisting of at least 22 contiguous amino acids selected from the amino acid sequence shown in SEQ ID NO:2. 3. An hphl fusion protein comprising a first protein segment and a second protein segment fiised together by means of a peptide bond, wherein the first protein segment consists of at least 8 contiguous amino acids of a human polyhomeotic 1 protein. 4. A preparation of antibodies which specifically bind to a human polyhomeotic 1 protein. 5. An isolated and purified subgenomic polynucleotide consisting of at least 10 contiguous nucieotides selected from the nucleotide sequence shown in SEQ ID NO:l. 6. An expression construct for expressing all or a portion of a human polyhomeotic 1 protein comprising: a promoter; and a polynucleotide segment encoding at least 8 contiguous amino acids of a human polyhomeotic 1 protein, wherein the polynucleotide segment is located downstream from the promoter, wherein transcription of the polynucleotide segment initiates at the promoter. 7. A homologously recombinant cell having incorporated therein a new transcription initiation unit, wherein the new transcription inititation unit comprises: (a) an exogenous regulatory sequence; (b) an exogenous exon; and (c) a splice donor site, wherein the transcription initiation unit is located upstream of a coding sequence of an hphl gene, wherein the exogenous regulatory sequence directs transcription of the coding sequence of the hphl gene. 8. A method of identifying neoplastic tissue of a human, comprising: comparing the expression of a polyhomeotic 1 gene in a first tissue of a human suspected of being neoplastic with the expression of a polyhomeotic 1 gene in a second tissue of the human which is normal, wherein underexpression of the human polyhomeotic 1 gene in the first tissue identifies the first tissue as being neoplastic. 9. A method to aid in the diagnosis or prognosis of neoplasia in a human, comprising: comparing a polyhomeotic 1 gene, mRNA, or protein in a first tissue of a human suspected of being neoplastic with a polyhomeotic 1 gene, mRNA, or protein in a second tissue of a human which is normal, wherein a difference between the polyhomeotic 1 genes, mRNAs, or proteins in the first and second tissues indicates neoplasia in the first tissue. 10. A method to aid in detecting a genetic predisposition to neoplasia in a human, comprising: comparing a polyhomeotic 1 gene, mRNA, or protein in the fetal tissue of a human with a wild-type human polyhomeotic 1 gene, mRNA, or protein, wherein a difference between the polyhomeotic 1 gene, mRNA, or protein in the fetal tissue of the human and the wild-type human polyhomeotic 1 gene, mRNA, or protein indicates a genetic predisposition to neoplasia in the human. 11. A method of identifying a human chromosome 12, comprising the steps of: contacting a preparation of metaphase human chromosomes with a nucleotide probe comprising at least 12 contiguous nucieotides selected from the nucleotide sequence shown in SEQ ID NO: 1; and detecting a chromosome which specifically hybridizes to the nucleotide probe, wherein a chromosome which specifically hybridizes to the nucleotide probe is identified as a human chromosome 12. 12. A therapeutic composition for restoring a wild-type human polyhomeotic 1 function to a cell which lacks that function, comprising: all or a portion of a wild-type human polyhomeotic 1 gene or expression product, wherein said all or a portion of the wild-type human polyhomeotic 1 gene or expression product is capable of restoring a wild-type polyhomeotic 1 function to a cell; and a pharmaceutically acceptable carrier. 13. A method of treating proliferative disorders, comprising the step of administering to a human a composition comprising all or a portion of a wild-type human polyhomeotic 1 gene or expression product, wherein said all or a portion of the wild-type human polyhomeotic 1 gene or expression is capable of restoring or enhancing a wild-type polyhomeotic 1 function to a cell. 14. A method of inducing a cell to differentiate, comprising the step of contacting a progenitor cell with a composition comprising all or a portion of a human polyhomeotic 1 gene or expression product, wherein said all or a portion of the human polyhomeotic 1 gene or expression product is capable of inducing differentiation of the c ceellll.

Inventors: RANDAZZO FILIPPO, RANDAZZO, FILIPPO
Applicants: CHIRON CORP, CHIRON CORPORATION
Application year: 1997
Main classification: C12N15
IPC codes: A61K38, C07K14, C12N15