APOPTOSIS--THE ROLES OF P35 AND IAP

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The ability of cells to undergo apoptosis (programmed cell death) is crucial to the normal development, differentiation and homeostasis of multicellular organisms and also provides a primary defense mechanism against viral invasion. Disruption of apoptotic pathway(s) results in oncogenesis in adults and abnormal development in embryos. Understanding the molecular basis by which cells identify and transduce the signals leading to cell death is thus central to defining the molecular basis of oncogenesis, growth and differentiation, and viral replication. The ability to modify cellular responses to apoptotic signals will enhance the ability to prevent, or possibly cure, a number of diseases including cancer and viral infections as well as provide insight into normal development and tissue maintenance. This project focuses on understanding the mechanism of action of two types of genes, baculovirus-derived p35 and iap genes, which block apoptosis in both invertebrates and vertebrates indicating that they act a crucial point in the apoptotic pathway. Based on the sequence of their polypeptide products, these two types of genes appear to act at distinctly differently points in the pathway. Iaps contain zinc binding domains characteristic of DNA binding proteins and are related to a p53-associated protein, MDM2; thus iaps probably act near the signal recognition point and respond specifically to the presence of damaged DNA or viral invasion. We will determine if iaps act by regulating the expression of other genes or act directly through nuclear interactions. In contrast, p35 appears to act directly in blocking apoptosis at the point governing the life vs. death decision. We will determine how p35 interacts with or abrogates the function of other genes governing this step (e.g., ced-3 (ICE) and ced-9 (bcl-2)). Characterization of p35 and iap interactions will provide insight into how viruses can counteract cellular apoptotic defense systems and may provide tools which can be used to control apoptotic pathways.