Hepatocellular carcinoma (HCC) is one of the leading causes of death from cancer on a worldwide basis. Chronic hepatitis B virus (HBV) infection is a well documented etiologic factor of HCC, accounting for the majority of cases in certain geographic areas where HBV carrier rates are high, such as in Southeast Asia and sub-Saharan Africa. The life cycle of the virus often depends on the dynamic interplay of various host functions in response to viral infection. Carcinogenesis, as induced by oncogenic viruses, is a complex and intricate process involving interactions of multiple host factors with the virus and/or the viral gene products. The HBV X gene likely plays a crucial role in the oncogenic potential of HBV. Since virus-host interactions are central to the pathogenesis of viral infection and host injury, we propose to focus our studies on the elucidation of the molecular basis of these interactions during HBV infection. We plan to study the molecular aspect of virus-cell interaction, identify and characterize the various cellular factors crucial to the functions of viral-encoded proteins. Key cellular genes whose protein products interact specifically with the HBV X (HBX) protein have been identified and cloned using the interaction cloning strategy in yeast. Two of the interacting proteins are subunits of proteasome complex and are likely important for the molecular mechanism of HBX function. The candidate gene product(s) will be characterized in great detail including complete sequence analysis, characterization of interaction in vitro and in vivo, identification of interacting domains, analysis of the physical basis of interaction, cellular and tissue distribution, and other potential interactive targets. Monoclonal or polyclonal antibodies against the proteins of interest will be developed as useful immunological and biochemical reagents. Second, we plan to explore the biochemical and molecular basis of these interactions as the basis for the biological functions of HBX. Structural and functional studies of interactions between HBX and its cellular targets will be performed using a variety of molecular and biochemical techniques. In particular, we plan to study the effects of HBX on proteasome functions in a variety of cellular processes, such as antigen presentation, protein turnover, and regulation of cellular transcription factors and oncoproteins.
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