Professor, Microbiology-Immunology; Feinberg School of Medicine
Cancer Cell Biology
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Cell cycle S phase induction and cell transformation by adenovirus E1A oncoprotein is dependent on its binding to and inactivating several host proteins. These are chromatin-associated proteins that play a role in gene regulation and include p400 (a transcription regulatory protein), p300/CBP (two highly homologous transcriptional co-activators and histone acetyl transferases), PCAF (p300/CBP associated factor) and the pocket family proteins pRb, p107 and p130. Thimmapaya laboratory focuses on the consequences of E1A interactions with the these cellular proteins on cell cycle G1-S transition, cell cycle progression, and cell transformation. His laboratory recently showed when p300 is depleted in quiescent cells, c-Myc and S phase are induced, and the induction of S phase is dependent on c-Myc induction. Similarly, in cells capable of conditionally over-expressing p300, serum-stimulated induction of c-Myc and S phase are repressed. In quiescent cells, repression of gene expression by p300 is specific for c-Myc (Proc. Natl. Acad. Sci. 2003, 100:9524). Depletion of CBP in quiescent cells also leads to the same effect, and surprisingly, cells that enter S phase do not complete cell cycle but stop at mid S phase and then apoptose suggesting that normal levels of both p300 and CBP are essential for c-Myc repression in quiescent cells, and the normal levels of both these proteins are also necessary for cell cycle progression. In other studies, Thimmapaya laboratory also showed that E1A induces c-Myc and S phase in quiescent cells only when it binds to p300 and Rb; binding to p400 is not linked to c-Myc induction or S phase. Thus, one of the consequences of E1A interaction with the p300 and Rb is to induce c-Myc that is critical for G1-S transition and cell transformation. These studies have broad implication in DNA tumor virus biology, in that one or more virus-encoded tumor antigens may induce c-Myc by binding to and inactivating the chromatin associated protein complexes.