The E1A oncogene of the DNA tumor virus adenovirus stimulates cell proliferation by inhibiting the actions of negative cell cycle regulators such as the Rb tumor suppressor protein. The p53 tumor suppressor protein responds to this growth deregulation with the induction of programmed cell death (apoptosis). Thus, p53 acts as a defense against viral infection and transformation through activation of apoptosis. The E1B oncogene of adenovirus cooperates with E1A in transformation and sustains viral infection by inhibiting E1A-induced, p53-dependent apoptosis. E1B possesses two independent mechanisms for disabling p53 function encoded by the l9K and 55K proteins. The 55K protein binds to and inhibits p53 directly, whereas the 19K protein is a member of the Bc1-2 family of apoptosis inhibitors. E1B 19K expression can block apoptosis induced not only by E1A and p53, but also by tumor necrosis factor, and Fas antigen, suggesting that it acts at a point central to the regulation of apoptosis by multiple pathways. We intend to establish the molecular basis for the regulation of apoptosis by the 19K protein through the characterization of 19K- interacting cellular proteins. The 19K protein associates with several proteins of either known or potential importance in the regulation of apoptosis. One 12K protein requires identification, whereas two others are known: the nuclear envelope structural protein lamin A and the Bc1-2 associated protein and antagonist Bax. The identity of the 12K protein will be determined as will its role in apoptosis. Lamins are required for nuclear assembly and organization and lamin destruction is an early event during apoptosis. We will investigate the role of lamins in the modulation of the nuclear events of apoptosis (chromatin condensation and DNA fragmentation) and how the association between 19K and lamins may maintain lamin functional integrity. The association between 19K and Bax suggests that 19K functions similarly to Bc1-2 through the interaction with the death promoter. The functional consequences of the interaction between 19K and Bax will be determined. By studying the interaction of the 19K protein with these cellular proteins we hope to understand how cell suicide instigated by growth deregulation is regulated. Defining the process of apoptosis at the molecular level is of basic importance to understanding development, cancer, degenerative diseases, and viral pathogenesis.
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