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Chronic infection by HBV is the leading cause of hepatocellular carcinoma in man. Several lines of evidence suggest that the viral transactivator HBx plays a critical role in the molecular pathogenesis of HBVrelated HCC. To study the actual impact of HBx and the mechanism of its action, we have recently cloned and characterized a set of X-sequences from HCC in patients with chronic infection by HBV. In the present study, we have compared the e ects of HBx and its naturally arising mutants on cell growth and viability. We report that HBx inhibits clonal outgrowth of cells and induces apoptosis by a p53-independent pathway. Furthermore, HBx expression induced a late G1 cell cycle block prior to their counterselection by apoptosis. Importantly, mutations in the HBx-gene evolving in hepatocellular carcinoma abolished both HBx-induced growth arrest and apoptosis. Using a panel of engineered mutants we have mapped the growth suppressive e ect of HBx to domains shown to be required for its transactivating function. Based on these results, we propose that abrogation of the anti-proliferative and apoptotic e ects of HBx by naturally occurring mutations might render the hepatocytes susceptible to uncontrolled growth and contribute to multistep hepatocarcinogenesis associated with HBV-infection.
Chronic infection by HBV is the leading cause of hepatocellular carcinoma in man. Several lines of evidence suggest that the viral transactivator HBx plays a critical role in the molecular pathogenesis of HBVrelated HCC. To study the actual impact of HBx and the mechanism of its action, we have recently cloned and characterized a set of X-sequences from HCC in patients with chronic infection by HBV. In the present study, we have compared the e ects of HBx and its naturally arising mutants on cell growth and viability. We report that HBx inhibits clonal outgrowth of cells and induces apoptosis by a p53-independent pathway. Furthermore, HBx expression induced a late G1 cell cycle block prior to their counterselection by apoptosis. Importantly, mutations in the HBx-gene evolving in hepatocellular carcinoma abolished both HBx-induced growth arrest and apoptosis. Using a panel of engineered mutants we have mapped the growth suppressive e ect of HBx to domains shown to be required for its transactivating function. Based on these results, we propose that abrogation of the anti-proliferative and apoptotic e ects of HBx by naturally occurring mutations might render the hepatocytes susceptible to uncontrolled growth and contribute to multistep hepatocarcinogenesis associated with HBV-infection.
Previously, we reported that adenovirus E1a protein behaves as a tumor suppressor in human cells. It apparently functions by transcriptionally inducing an array of epithelial cell adhesion genes, while repressing other cell-type speci®c genes, thus producing an epithelial phenotype. Concomitantly, the cells become sensitive to anoikis (apoptosis of epithelial cells detached from extracellular matrix), potentially causing tumor suppression. E1a protein interacts with the nuclear acetylases p300, CBP and P/CAF, and also with the co-repressor protein CtBP. In this study, we have determined the role of these interactions in E1a's phenotypic e ects on human tumor cells. The results indicate that E1a's interaction with CtBP activates at least three epithelial cell adhesion gene promoters. The E-cadherin repressor appeared to be the CtBP-interacting protein d EF1/ZEB, which bound the ras-repressible E-boxes of the E-cadherin promoter. The E1a ± CtBP interaction also contributed to anoikissensitization. E1a's interactions with the nuclear acetylases conferred epithelial morphologies but did not activate epithelial genes. These latter interactions did not sensitize tumor cells to anoikis but nevertheless conferred tumor suppression. These results implicate CtBP as an antagonist of the epithelial phenotype and anoikis. They also indicate a new but unde®ned role for nuclear acetylases in maintaining the transformed phenotype. Oncogene (2000) 19, 3823 ± 3828.
This past decade has witnessed the remarkable advances in the understanding of the role of the erbB2 gene in cancers and the stunning progress in developing targeted therapies for erbB2-overexpressing cancers. Activation of the ErbB2 receptor signaling pathways can enhance various metastasis-associated properties that lead to an increase of cancer metastasis. Additionally, ErbB2 overexpression confers therapeutic resistance via receptor-mediated antiapoptotic signals. To limit these disastrous e ects of the overexpressed ErbB2, various ErbB2-blocking strategies have been developed in the laboratories and several have been tested in clinical trials or approved as therapies for ErbB2 overexpressing cancers. In this article, we will discuss the detrimental e ects of the erbB2 gene in cancers, with a focus on breast cancer. We will also outline ErbB2-targeting strategies as potential therapies for ErbB2-overexpressing cancers. Progress in understanding the molecular biology of ErbB2 and in molecular-based treatment of ErbB2-overexpressing tumors will bring great bene®ts to cancer patients. Oncogene (2000) 19, 6115 ± 6121.
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