Cellular Pathways Involved in Cell Transformation and Oncogenesis
Cancer evolves from a cell that undergoes uncontrolled proliferation and migration. It is now clear that most cancers are initiated by genetic changes in the cell's genome, among which mutations in genes known as proto-oncogenes and tumor suppressors within such cell are the key to its malignant transformation. Genetic and biochemical studies of these genes have revealed some major events that cause normal cells to become cancerous; these include inactivating both tumor suppressors p53 and pRb pathways, activating oncogenes such as ras, and telomere maintenance. Studies of viral oncogenes have contributed significantly to the advances in understanding cancer. Indeed, it is now clear that the major role of viral oncogenes is to transform cells by inactivating p53 and pRb pathways. Thus, several well-studied DNA tumor viruses encode proteins that target and inactivate p53 and pRb; the best known examples are the simian virus 40 (SV40) large-T antigen, the human papillomavirus-16 E6 and E7 oncoproteins, and the adenovirus E1A and E1B proteins. In the case of adenovirus, E1A oncoproteins target the pRb pathway, whereas E1B 55-kDa oncoprotein inactivates p53. Adenovirus-induced cell transformation requires the cooperation of both E1A and E1B. The E1B 55-kDa protein binds to p53 in adenovirus transformed cells and inhibits p53-mediated transcriptional transactivation, the key function by which p53 exerts its tumor suppressor function. We have shown recently that E1B can specifically inhibit p53 acetylation by cellular transcription coactivator and acetylase PCAF. As acetylation of p53 plays a key role in regulating p53 function, inhibition of p53 acetylation represents a new mechanism by which viral oncoproteins repress p53 function. E1B also appears to abrogate cellular machinery regulating mitotic cell division, thereby causing abnormal cell division and genome instability. Additionally, E1B is involved in several other processes, such as transcriptional repression, RNA transport, apoptosis and chromosome fragility. These results suggest that E1B 55-kDa protein target multiple vital cellular pathways. Our current research has two major objectives: (1) to understand the biochemical mechanisms by which viral oncoproteins inactivate tumor suppressor p53 and related proteins and (2) to reveal novel cellular regulatory pathways involved in growth control and the biochemical mechanisms by which viral oncoproteins perturb such pathways and the implications for cell transformation and oncogenesis. Our long-term goal is to uncover the inner-working of fundamental cellular pathways involved in regulating cell growth and proliferation and how dysfunction of such pathways may lead to uncontrolled cell growth and cancer.

We employ cellular, biochemical and genetic approaches to identify key pathways targeted by viral transforming proteins. Current projects include: (1) yeast-two hybrid screen of human cDNA libraries for E1B-binding cellular proteins, (2) elucidating the roles of acetylation of tumor suppressor p53 and related proteins such as p73 for their function through mutagenesis and luciferase reporter gene assay, (3) analysis of biochemical mechanism by which E1B represses transcription, (4) global pattern of gene expression in cells with E1B expression using DNA microarray technology.

Dr. Liao joined UF faculty in 2000. He was an assistant professor at the University of Sherbrooke, Canada from 1997 to 2000. He conducted his postdoctoral training at Yale University School of Medicine from 1994 to1997 and received his Ph.D. from the University of British Columbia, Canada in 1993, M.S. from Peking University, China in 1986 and B.S. from Hunan University, China in 1983.