Cancer arises through specific genetic changes in somatic cells. Major events include inactivating both p53 and pRb pathways, activating oncogenes such as ras, and telomere maintenance. Such genetic events may also be reflected in cells transformed by tumor viruses. For example, several viral oncogenes, such as the simian virus 40 large-T antigen, the human papillomavirusl6 E6 and E7 oncoproteins, and the adenovirus (Ad) E1A and E1B proteins, can effectively inactivate the p53 and pRb pathways. In addition, these multifunctional viral oncogenes can perturb other cell pathways, which may contribute to cell transformation. p53 is a prototypic tumor suppressor that is frequently mutated in diverse human cancers. It exerts its tumor suppression function largely through transactivation of genes containing specific p53- binding DNA sequences within their promoters. The p53 target genes are involved in cell cycle arrest and apoptosis, two major mechanisms in tumor suppression. Viral oncoproteins employ different strategies to inactivate p53, ranging from interference with p53-DNA interaction to promoting p53 degradation. We demonstrated recently that Ad E1B 55-kDa proteins repress p53 transactivation by specifically inhibiting acetylation of p53 by acetylase PCAF. As p53 acetylation at specific lysine residues by PCAF and p300 is crucial for its transactivation function and its ability to suppress cell transformation, inhibition of p53 acetylation by E1B impairs its function. We will determine the biological significance of p53 acetylation by these acetylases and mechanism(s) by which E1B inhibits p53 acetylation. We have found that E1B binds to PCAF and p300. We will determine the importance of such interactions for E1B to inhibit p53 acetylation by these acetylases, and how E1B may affect their functions. We also found that E1B interferes with p53-dependent and -independent cell cycle checkpoints. We will determine potential mechanisms underlying such interference. Additionally, p53 protein levels are elevated in cells expressing EIB, which may be a consequence of perturbing ubiquitin-dependent proteolysis by E1B, as we found that it binds to a variant of UbcH7, a ubiquitin conjugating enzyme that is involved in ubiquitination of certain cellular proteins including p53. We will elucidate how E1B perturbs this pathway. These studies will enhance our understanding of cell transformation and cancer.
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