bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hormone-Induced Chromosomal Instability in p53-Null Mammary Epithelium
Authors: Pati Debananda , Haddad Bassem R. , Haegele Albert , Thompson Henry , Kittrell Frances S. , Shepard Anne , Montagna Cristina , Zhang Nenggang , Ge Gouqing , Otta Subhendu Kumar , McCarthy Maureen , Ullrich Robert L. , Medina Daniel 
Published: September 2005

Abstract
The absence of p53 function increases risk for spontaneous tumorigenesis in the mammary gland. Hormonal stimulation enhances tumor risk in p53-null mammary epithelial cells as well as the incidence of aneuploidy. Aneuploidy appears in normal p53-null mammary epithelial cells within 5 weeks of hormone stimulation. Experiments reported herein assessed a possible mechanism of hormone-induced aneuploidy. Hormones increased DNA synthesis equally between wild-type (WT) and p53-null mammary epithelial cells. There were two distinct responses in p53-null cells to hormone exposure. First, Western blot analysis demonstrated that the levels of two proteins involved in regulating sister chromatid separation and the spindle checkpoint, Mad2 and separase (ESPL1) were increased in null compared with WT cells. In contrast, the levels of securin and Rad21 proteins were not increased in hormone-stimulated p53-null compared with WT cells. ESPL1 RNA was also increased in p53-null mouse mammary cells in vivo by 18 h of hormone stimulation and in human breast MCF7 cells in monolayer culture by 8 h of hormone stimulation. Furthermore, both promoters contained p53 and steroid hormone response elements. Mad2 protein was increased as a consequence of the absence of p53 function. The increase in Mad2 protein was observed also at the cellular level by immunohistochemistry. Second, hormones increased gene amplication in the distal arm of chromosome 2, as shown by comparative genomic hybridization. These results support the hypothesis that hormone stimulation acts to increase aneuploidy by several mechanisms. First, by increasing mitogenesis in the absence of the p53 checkpoint in G2, hormones allow the accumulation of cells that have experienced chromosome missegregation. Second, the absolute rate of chromosome missegregation may be increased by alterations in the levels of two proteins, separase and Mad2, which are important for maintaining chromosomal segregation and the normal spindle checkpoint during mitosis.
Cyr61 Is Overexpressed in Gliomas and Involved in Integrin-Linked Kinase-Mediated Akt and β-Catenin-TCF/Lef Signaling Pathways
Authors: Xie Dong , Yin Dong , Tong Xiangjun , O’Kelly James , Mori Akio , Miller Carl , Black Keith , Gui Dorina , Said Johathan W. , Koeffler H. Phillip 
Published: September 2005

Abstract
Cyr61 is a member of the CCN family of growth factors; these proteins are secreted and can act as ligands of distinct integrins. We show that Cyr61 can enhance tumorigenicity of glioma cells acting through activated integrin-linked kinase (ILK) to stimulate β-catenin-TCF/Lef and Akt signaling pathways. Overexpression of Cyr61 occurred in highly tumorigenic glioma cell lines and in 68% of the most malignant glioblastoma multiforme brain tumors. Forced expression of Cyr61 in U343 glioma cells accelerated their growth in liquid culture, enhanced their anchorage-independent proliferation in soft agar, and significantly increased their ability to form large, vascularized tumors in nude mice. Overexpression of Cyr61 in the U343 cells led to the up-regulation of distinct integrins, including β1 and ανβ3, which have been shown to interact with Cyr61 and ILK. The activity of ILK was increased dramatically in these cells. Overexpression of Cyr61 also resulted in the phosphorylation of glycogen synthase kinase-3β and accumulation and nuclear translocation of β-catenin, leading to activation of the β-catenin-TCF/Lef-1 signaling pathway. Furthermore, forced expression of Cyr61 in the glioma cells activated phosphatidylinositol 3′-kinase pathway, resulting in prominent phosphorylation of Akt and the antiapoptotic protein Bad. Cyr61 appears to stimulate several signaling pathways in the development of gliomas.
A Mutant High-Density Lipoprotein Receptor Inhibits Proliferation of Human Breast Cancer Cells
Authors: Cao Wen M. , Murao Koji , Imachi Hitomi , Yu Xiao , Abe Hiroshi , Yamauchi Akira , Niimi Michio , Miyauchi Akira , Wong Norman C. W. , Ishida Toshihiko 
Published: September 2005

Abstract
High-density lipoprotein (HDL) stimulates the growth of many types of cells, including those of breast cancer. High levels of HDL are associated with an increased risk of breast cancer development. A scavenger receptor of the B class (SR-BI)/human homolog of SR-BI, CD36, and LIMPII analogous-1 (CLA-1) facilitates the cellular uptake of cholesterol from HDL and thus augments cell growth. Furthermore, HDL is also believed to have antiapoptotic effects on various cell types, and this feature adds to its ability to promote cell growth. These collaborative roles of HDL and CLA-1 prompted us to assess the function of these components on human breast cancer cells. In this study, we created a mutant CLA-1 (mCLA) that lacked the COOH-terminal tail to determine its potential role in breast cancer cell growth. Expression of mCLA inhibited the proliferation of breast cancer cell line MCF-7. This inhibitory action of mCLA required the transcriptional factor activator protein-1 (AP-1), and the mutant receptor also affected the antiapoptotic features of HDL. The effect of HDL on AP-1 activation and [3H]thymidine incorporation was abrogated by wortmannin, a specific inhibitor of phosphoinositide 3-kinase. Furthermore, the dominant negative mutant of Akt abolished the ability of HDL to activate AP-1. These findings raise the possibility that the inhibitors of the effects of HDL may be of therapeutic value for breast cancer.
Nickel Compounds Act through Phosphatidylinositol-3-kinase/Akt-Dependent, p70S6k-Independent Pathway to Induce Hypoxia Inducible Factor Transactivation and Cap43 Expression in Mouse Epidermal Cl41 Cells
Authors: Li Jingxia , Davidson Gerard , Huang Yi , Jiang Bing-Hua , Shi Xianglin , Costa Max , Huang Chuanshu 
Published: September 2005

Abstract
Nickel compounds are a somewhat unique class of carcinogens. Previous studies have demonstrated that NiCl2 exposure leads to marked induction of hypoxia inducible factor 1 (HIF-1) in human osteosarcoma and BALB/c 3T3 cells, a transcription factor that has been considered to play an important role in tumor promotion and progression. However, the signal transduction pathways leading to HIF-1 induction are not well understood. The present study indicated that exposure of mouse epidermal Cl41 cells to either Ni3S2 or NiCl2 resulted in activation of phosphatidylinositol 3-kinase (PI-3K), Akt, and p70 S6 kinase (p70S6k). Inhibition of PI-3K, Akt, and p70S6k by overexpression of a dominant-negative mutant of PI-3K (Δp85) impaired nickel-induced HIF-1 transactivation. Furthermore, an overexpression of the dominant-negative Akt mutant (Akt-T308A/S473A) blocked nickel-induced Akt phosphorylation and HIF-1 transactivation, whereas inhibition of p70S6k activation by pretreatment of cells with rapamycin did not show significant inhibitory effects on HIF-1 transactivation induced by nickel compounds. Consistent with HIF-1 transactivation, inhibition of the PI-3K/Akt pathway by either overexpression of Δp85 or Akt-T308A/S473A caused dramatic inhibition of Cap43 protein expression induced by nickel compounds, whereas pretreatment of cells with rapamycin did not exhibit inhibition of Cap43 induction. These results demonstrated that nickel compounds induce HIF-1 transactivation and Cap43 protein expression through a PI-3K/Akt-dependent and p70S6k-independent pathway. This study should help us understand the signal transduction pathways involved in the carcinogenic effects of nickel compounds.
A Constitutively Active Dioxin/Aryl Hydrocarbon Receptor Promotes Hepatocarcinogenesis in Mice
Authors: Moennikes Oliver , Loeppen Sandra , Buchmann Albrecht , Andersson Patrik , Ittrich Carina , Poellinger Lorenz , Schwarz Michael 
Published: September 2005

Abstract
The dioxin/aryl hydrocarbon receptor (AhR) functions as a ligand-activated transcription factor regulating transcription of a battery of genes encoding enzymes involved in drug metabolism. Known ligands include polycyclic aromatic hydrocarbons, certain polychlorinated biphenyls, and the polyhalogenated dioxins including 2,3,7,8-tetrachlorodibenzo-p-dioxin. Both polyhalogenated biphenyls and 2,3,7,8-tetrachlorodibenzo-p-dioxin are potent promoters of rodent hepatocarcinogenesis in two-stage initiation-promotion experiments. Although several lines of evidence indicate the involvement of the AhR in toxic effects mediated by polyhalogenated biphenyls and dioxins, its involvement in tumor promotion has not been unequivocally proven. In the present study, a transgenic mouse line expressing a constitutively active AhR (CA-AhR) has been used to investigate the role of the AhR in hepatocarcinogenesis. Male AhR wild-type and CA-AhR-transgenic B6C3F1-mice were treated with a single injection of the hepatocarcinogen N-nitrosodiethylamine at 6 weeks of age and were subsequently kept untreated on control diet. Thirty five weeks after carcinogen treatment, mice were sacrificed, and the prevalence and multiplicity of liver tumors were determined. Whereas only 1 small liver tumor was observed in 15 AhR-wild-type mice, 19 tumors (two &gt;1 cm in diameter) were present in 18 CA-AhR-transgenic mice. This result demonstrates the oncogenic potential of the activated AhR and implicates an important role of the receptor in promotion of hepatocarcinogenesis. A microarray-based gene expression-profiling analysis revealed down-regulation in the liver of CA-AhR-transgenic mice of a cluster of genes encoding heat shock proteins, including GRP78/BiP, Herp1, Hsp90, DnaJ (Hsp40) homologue B1, and Hsp105, which are important for protein folding and quality control.
Prostate Pathology of Genetically Engineered Mice: Definitions and Classification. The Consensus Report from the Bar Harbor Meeting of the Mouse Models of Human Cancer Consortium Prostate Pathology Committee
Authors: Shappell Scott B. , Thomas George V. , Roberts Richard L. , Herbert Ron , Ittmann Michael M. , Rubin Mark A. , Humphrey Peter A. , Sundberg John P. , Rozengurt Nora , Barrios Roberto , Ward Jerrold M. , Cardiff Robert D. 
Published: September 2005

Abstract
The Pathological Classification of Prostate Lesions in Genetically Engineered Mice (GEM) is the result of a directive from the National Cancer Institute Mouse Models of Human Cancer Consortium Prostate Steering Committee to provide a hierarchical taxonomy of disorders of the mouse prostate to facilitate classification of existing and newly created mouse models and the translation to human prostate pathology. The proposed Bar Harbor Classification system is the culmination of three meetings and workshops attended by various members of the Prostate Pathology Committee of the Mouse Models of Human Cancer Consortium. A 2-day Pathology Workshop was held at The Jackson Laboratory in Bar Harbor, Maine, in October 2001, in which study sets of 93 slides from 22 GEM models were provided to individual panel members. The comparison of mouse and human prostate anatomy and disease demonstrates significant differences and considerable similarities that bear on the interpretation of the origin and natural history of their diseases. The recommended classification of mouse prostate pathology is hierarchical, and includes developmental, inflammatory, benign proliferative, and neoplastic disorders. Among the neoplastic disorders, preinvasive, microinvasive, and poorly differentiated neoplasms received the most attention. Specific criteria were recommended and will be discussed. Transitions between neoplastic states were of particular concern. Preinvasive neoplasias of the mouse prostate were recognized as focal, atypical, and progressive lesions. These lesions were designated as mouse prostatic intraepithelial neoplasia (mPIN). Some atypical lesions were identified in mouse models without evidence of progression to malignancy. The panel recommended that mPIN lesions not be given histological grades, but that mPIN be further classified as to the absence or presence of documented associated progression to invasive carcinoma. Criteria for recognizing microinvasion, for classification of invasive gland-forming adenocarcinomas, and for characterizing poorly differentiated tumors, including neuroendocrine carcinomas, were developed and are discussed. The uniform application of defined terminology is essential for correlating results between different laboratories and models. It is recommended that investigators use the Bar Harbor Classification system when characterizing new GEM models or when conducting experimental interventions that may alter the phenotype or natural history of lesion progression in existing models.
p14ARF Expression Increases Dihydrofolate Reductase Degradation and Paradoxically Results in Resistance to Folate Antagonists in Cells with Nonfunctional p53
Authors: Magro Pellegrino G. , Russo Angelo J. , Li Wei-Wei , Banerjee Debabrata , Bertino Joseph R. 
Published: September 2005

Abstract
The p14ARF protein, the product of an alternate reading frame of the INK4A/ARF locus on human chromosome 9p21, disrupts the ability of MDM2 to target p53 for proteosomal degradation and causes an increase in steady-state p53 levels, leading to a G1 and G2 arrest of cells in the cell cycle. Although much is known about the function of p14ARF in the p53 pathway, not as much is known about its function in human tumor growth and chemosensitivity independently of up-regulation of p53 protein levels. To learn more about its effect on cellular proliferation and chemoresistance independent of p53 up-regulation, human HT-1080 fibrosarcoma cells null for p14ARF and harboring a defective p53 pathway were stably transfected with p14ARF cDNA under the tight control of a doxycycline-inducible promoter. Induction of p14ARF caused a decrease in cell proliferation rate and colony formation and a marked decrease in the level of dihydrofolate reductase (DHFR) protein. The effect of p14ARF on DHFR protein levels was specific, because thymidylate kinase and thymidylate synthase protein levels were not decreased nor were p53 or p21WAF1 protein levels increased. The decrease in DHFR protein was abolished when the cells were treated with the proteasome inhibitor MG132, demonstrating that p14ARF augments proteasomal degradation of the protein. Surprisingly, induction of p14ARF increased resistance to the folate antagonists methotrexate, trimetrexate, and raltitrexed. Depletion of thymidine in the medium reversed this resistance, indicating that p14ARF induction increases the reliance of these cells on thymidine salvage.
Endothelial P-Selectin as a Target of Heparin Action in Experimental Melanoma Lung Metastasis
Authors: Ludwig Ralf J. , Boehme Beatrice , Podda Maurizio , Henschler Reinhard , Jager Elke , Tandi Christa , Boehncke Wolf-Henning , Zollner Thomas M. , Kaufmann Roland , Gille Jens 
Published: September 2005

Abstract
Spontaneous and experimental metastasis can be effectively inhibited by the widely used anticoagulant heparin in different tumor models. At the cellular level, many of the antimetastatic effects of heparin in vivo are due to its action on P-selectin-mediated binding. Whereas previous attention has focused on P-selectin-dependent tumor-cell–platelet interactions in blood-borne metastasis, we sought to address the potential contribution of endothelial P-selectin expression to adhesive events between the microvasculature and melanoma cells in vivo. Transplantation of bone marrow from P-selectin-deficient into wild-type mice conveyed inhibition of ex-perimental melanoma metastasis. However, the extent to which bone marrow-conferred lack of platelet P-selectin expression attenuated melanoma lung metastasis was significantly less than that seen in P-selectin-deficient mice, suggesting that endothelial P-selectin expression may additionally contribute to formation of hematogenous metastases. This assumption was supported by our intravital microscopy studies, in which a significant proportion of melanoma cells were capable of directly interacting with postcapillary venules of the murine ear in a P-selectin-dependent manner. Heparin not only inhibits P-selectin-mediated melanoma cell rolling but also attenuates melanoma metastasis formation in vivo, further supporting the concept that endothelial P-selectin expression may represent an additional target of heparin action in experimental melanoma lung metastasis.
Transdominant ΔTAp73 Isoforms Are Frequently Up-regulated in Ovarian Cancer. Evidence for Their Role as Epigenetic p53 Inhibitors
in Vivo
Authors: Concin Nicole , Becker Kirsten , Slade Neda , Erster Susan , Mueller-Holzner Elizabeth , Ulmer Hanno , Daxenbichler Guenter , Zeimet Alain , Zeillinger Robert , Marth Christian , Moll Ute M. 
Published: September 2005

Abstract
Despite strong homology, the roles of TP53 and TP73 in tumorigenesis seem to be fundamentally different. In contrast to TP53, tumor-associated overexpression of TP73 in many different cancers, combined with virtual absence of inactivating mutations and lack of a cancer phenotype in the TP73 null mouse are inconsistent with a suppressor function but instead support an oncogenic function. The discovery of NH2-terminally truncated p73 isoforms, collectively called ΔTAp73, is now the focus of intense interest because they act as potent transdominant inihibitors of wild-type p53 and transactivation-competent TAp73. Therefore, establishing deregulated ΔTAp73 expression in tumors could be the crucial link to decipher which of the two opposing roles of this bipolar gene is the biologically relevant one. This study is the largest to date and encompasses 100 ovarian carcinomas with complete expression profile of all NH2-terminal isoforms, discriminating between TAp73 and ΔTAp73 (ΔNp73, ΔN′p73, Ex2p73, and Ex2/3p73) by isoform-specific real-time reverse transcription-PCR. We find that the set of NH2-terminal p73 isoforms distinguishes ovarian cancer patients from healthy controls and thus is a molecular marker for this diagnosis. Ovarian cancers strongly and almost universally overexpress ΔN′p73 compared with normal tissues (95% of cancers). About one-third of tumors also exhibit concomitant up-regulation of the antagonistic TAp73, whereas only a small subgroup of tumors overexpress ΔNp73. Thus, deregulation of the E2F1-responsive P1 promoter, rather than the alternate P2 promoter, is mainly responsible for the production of transdominant p53/TAp73 antagonists in ovarian cancer. Tumor stage, grade, presence of metastases, p53 status, and residual disease after resection are significant prognostic markers for overall and recurrence-free survival. A trend is found for better overall survival in patients with low expression of ΔN′p73/ΔNp73, compared with patients with high expression. A strong correlation between deregulated ΔTAp73 and p53 status exists. p53 wild-type cancers exhibit significantly higher deregulation of ΔN′p73, ΔNp73, and Ex2/3p73 than p53 mutant cancers. This data strongly supports the hypothesis that overexpression of transdominant p73 isoforms can function as epigenetic inhibitors of p53 in vivo, thereby alleviating selection pressure for p53 mutations in tumors.
In Vivo
Imaging of HIV Protease Activity in Amplicon Vector-transduced Gliomas
Authors: Shah Khalid , Tung Ching-Hsuan , Chang Chung-Hsun , Slootweg Eric , O’Loughlin Terence , Breakefield Xandra O. , Weissleder Ralph 
Published: September 2005

Abstract
In vivo imaging of endogenously expressed mammalian proteases has been useful for the detection of cancer and preneoplastic lesions, for staging of inflammatory and autoimmune diseases, and for testing the efficacy of novel protease inhibitors. Here we report on the synthesis of a novel imaging probe that is specific for HIV-1 protease (PR). The probe was designed to be biocompatible, i.v. injectable, and detectable by fluorescence imaging. Human Gli36 glioblastoma cells infected with an human simplex virus amplicon vector expressing HIV-1PR showed specific fluorescence activation, an effect that could be inhibited by the HIV-1PR inhibitor, indinavir. The transfer of the HIV-1PR marker gene could be detected in vivo after intratumoral delivery of the human simplex virus-amplicon vector. These results are the first proof of principle that viral proteases can directly be imaged in vivo. These findings may be directly applicable in using viral protease expression as a transgene marker in tumor therapy and may have implications in testing the efficacy of HIV-1PR inhibitors in vivo.
Specific Histone Patterns and Acetylase/Deacetylase Activity at the Breakpoint-Cluster Region of the Human
MLL
Gene
Authors: Khobta Andriy , Carlo-Stella Carmelo , Capranico Giovanni 
Published: September 2005

Abstract
The MLL gene breakpoint-cluster region (BCR) is a known hot-spot for chromosomal translocations in human leukemias. We mapped core histone modifications and histone H1 along the MLL gene in Jurkat cells and human CD34+ progenitor blood cells by chromatin immunoprecipitation. Within the BCR, we found specific histone patterns that were different from other genomic regions and a histone H1-free fragment at the telomeric end. Core histone acetylase/deacetylase activities were also found within the BCR. In the studied cell models, chromatin components at the MLL BCR suggest an asymmetric organization that may influence early molecular events eventually leading to chromosomal translocations.
Expression of
POT1
is Associated with Tumor Stage and Telomere Length in Gastric Carcinoma
Authors: Kondo Tomohiro , Oue Naohide , Yoshida Kazuhiro , Mitani Yoshitsugu , Naka Kazuhito , Nakayama Hirofumi , Yasui Wataru 
Published: September 2005

Abstract
Pot1, a telomere end-binding protein in fission yeast and human, is proposed not only to cap telomeres but also to recruit telomerase to the ends of chromosomes. No study has been performed regarding Pot1 expression status in human cancers. Thus, we examined POT1 mRNA expression in 51 gastric cancer (GC) tissues and evaluated telomere length and 3′ telomeric overhang signals in 20 of the 51 GC tissues. Quantitative reverse transcription-PCR analysis showed that POT1 expression levels in the tumor relative to those in nonneoplastic mucosa (T/N ratio) were significantly higher in stage III/IV tumors than in stage I/II tumors (P = 0.005). Down-regulation of POT1 (T/n &lt; 0.5) was observed more frequently in stage I/II GC (52.4%, 11 of 21) than in stage III/IV GC (23.3%, 7 of 30; P = 0.033), whereas up-regulation of POT1 (T/n &gt; 2.0) was observed more frequently in stage III/IV GC (33.3%, 10 of 30) than in stage I/II GC (9.5%, 2 of 21; P = 0.048). POT1 expression levels showed decreased in accordance with telomere shortening (r = 0.713, P = 0.002). In-gel hybridization analysis showed that 3′ telomeric overhang signals decreased in accordance with decreases in POT1 expression levels (r = 0.696, P = 0.002) and telomere shortening (r = 0.570, P = 0.013). Reduced POT1 expression was observed in GC cell lines with telomeres shortened by treatment with azidothymidine. In addition, inhibition of Pot1 by antisense oligonucleotides led to telomere shortening as well as inhibition of telomerase activity in GC cells. Moreover, inhibition of Pot1 decreased 3′ overhang signals and increased the frequency of anaphase bridge (P = 0.0005). These data suggest that Pot1 may play an important role in regulation of telomere length and that inhibition of Pot1 may induce telomere dysfunction. Moreover, changes in POT1 expression levels may be associated with stomach carcinogenesis and GC progression.