GROWTH AND APOPTOSIS IN HBV ASSOCIATED LIVER CANCER

乙型肝炎相关肝癌的生长和细胞凋亡

• 批准号: 2654169
• 负责人: MARK A FEITELSON
• 金额: $ 31.88万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-04-14 至 2000-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2654169
• 关键词: apoptosis; cell growth regulation; gene mutation; genetic promoter element; hepatitis B antigens; hepatitis B virus group; human tissue; laboratory rat; liver cells; liver neoplasms; neoplasm /cancer pharmacology; oncoproteins; plasmids; transcription factor; transfection; transfection /expression vector; tumor suppressor proteins; viral carcinogenesis

DESCRIPTION: The objective of this proposal is to determine whether hepatitis B virus (HBV) encoded x antigen (HBxAg) triggers apoptosis, prevents apoptosis, and/or contributes to the proliferation of differentiated mammalian hepatocytes. This objective is based upon preliminary data demonstrating the centrality of HBxAg to hepatocellular transformation (escape from apoptosis?) and the availability of primary hepatocytes to study the relationship of HBxAg functions upon cell viability and growth. The fact that HBxAg binds and inactivates the tumor suppressor product, p53, that HBxAg stimulates de novo protein synthesis by trans-activation, and that it stimulates protein kinase C (PKC), highlights candidate functions which may allow some virus infected cells to persist during chronic infection. In addition, the fact that colchicine or vinblastine induce apoptosis in primary rat hepatocytes, which requires de novo protein synthesis, stimulation of PKC, and is associated with a transient spike of p53 mRNA (which coincides with a commitment to apoptosis), strongly suggests that this system can be exploited to examine the overlapping properties of HBxAg which may effect the same signal transduction pathways which are operative in apoptosis. Hence, the first specific aim will test the hypothesis that HBxAg alters the sensitivity of primary rat hepatocytes to drug induced apoptosis. This will be done by asking whether HBxAg can replace or complement other oncogene products, such as adenovirus E1A or E1B, mutant p53, and activated ras in overcoming apoptosis, and in some cases, stimulating cell growth. Selected HBxAg mutants will be used to identify the properties of HBxAg which correlate with apoptosis and/or proliferation. Given that HBxAg binds to p53, and the centrality of p53 to apoptosis, the second specific aim will test the hypothesis that HBxAg acts by altering p53 dependent biochemical pathways important to hepatocellular growth and apoptosis. These experiments will test whether HBxAg/p53 complex formation alters the conformation, phosphorylation state, and/or cellular localization of p53, and whether such changes correlate with changes in the ability of p53 to trans- activate cognate promoters or to bind specific cellular polypeptides (e.g., mdm-2). Again, selected HBxAg mutants which fail to complex with or alter p53 function will be used to identify the characteristics of the complexes which are likely to alter the p53 associated signal transduction pathways in hepatocytes important to the regulation of apoptosis. In addition, they will provide a fundamental understanding of hepatocellular growth and/or apoptosis associated with HBV infection on the cellular and molecular levels. This work will also provide opportunities for the establishment of cellular and biochemical assays capable of screening drugs which effect pathways important to the pathogenesis of chronic HBV infection and the development of hepatocellular carcinoma.

描述：本提案的目的是确定是否