Penelope J. Duerksen-Hughes, PhD
Our laboratory studies the interactions between viruses and the hosts they infect, focusing on the mechanisms by which HPV 16, a virus that causes cervical carcinoma, avoids elimination by the host immune system. Papillomavirus infections typically result in little or no immune activation, and thus the virus can persist in the host for long periods of time. Our laboratory has shown that the viral E6 oncoprotein is responsible for much of this immune evasion. E6 functions, at least in part, by protecting the cells that express it from host-generated apoptotic responses such as those triggered by TNF, Fas, and TRAIL. Each of these apoptotic pathways involves several signaling molecules, and E6 works by binding to some, though not all, of them. One possible consequence of such binding is the blocking of signal transmission, such as we observed following the binding of E6 to the TNF receptor TNF R1. This prevents TNF R1 from binding to the next molecule in the pathway, TRADD. Another possible consequence is the degradation of signaling intermediates, noted following the binding of E6 to FADD or to procaspase 8. We are working to further define these interactions with a long-term goal of developing small molecule inhibitors of such binding, which would have the potential to function as therapeutic reagents.
Interestingly, E6 occurs in two versions due to alternative splicing. These two splicing variants offer the virus additional diversity in immune evasion mechanisms. For example, while the full-length version is required to protect cells from apoptosis triggered through Fas, both the truncated and the full-length versions can provide protection from TNF. Also, while both versions bind to procaspase 8, only the full-length version accelerates its degradation.
Finally, we have used microarray analysis to discover that E6 affects the cellular responses to apoptotic signals induced by DNA damage by changing the expression patterns of genes involved in the early response, and these studies have identified a number of potential new targets for the development of chemotherapeutic reagents. Together, our results indicate that HPV 16 has acquired a number of mechanisms designed to thwart host-triggered apoptosis and to ensure the survival of the virus and its host cell. A clear understanding of these host-virus interactions will facilitate efforts to develop novel and effective therapeutic approaches.Yang J, Duerksen-Hughes PJ. A new approach to identifying genotoxic carcinogens: p53-induction as an indicator of genotoxic damage. Carcinogenesis 19(6):1117-1125, 1998.
Duerksen-Hughes, PJ, Yang J, Ozcan O. p53-Induction as a genotoxic test for twenty-five chemicals undergoing in vivo carcinogenicity testing. Env. Health Perspectives 107:805-812, 1999.
Duerksen-Hughes PJ, Yang J, Schwartz SB. The HPV 16 E6 gene blocks TNF-mediated cytolysis in mouse fibroblast LM cells. Virology 264:55-65, 1999.
Yang J, Duerksen-Hughes PJ. Activation of a p53 -independent, sphingolipid-mediated cytolytic pathway in p53-negative mouse fibroblast cells treated with N-methyl-N-nitro-N-nitrosoguanidine. J. Biol. Chem. 276:27129-27135, 2001.
Filippova M, Song H, Connolly JL, Dermody TS, Duerksen-Hughes PJ. The human papillomavirus 16 E6 protein binds to TNF R1 and protects cells from TNF-triggered apoptosis. J. Biol. Chem. 277:21730-21739, 2002.
Yang J, Yu Y, Duerksen-Hughes PJ . Protein kinases and their involvement in the cellular responses to genotoxic stress. Mutation Research 543:31-58, 2003.
Filippova M, Duerksen-Hughes PJ . Inorganic and dimethylated arsenic species induce cellular p53. Chemical Research in Toxicology 16:423-431, 2003.
Yang J, Yu Y, Hamrick HE, Duerksen-Hughes PJ . ATM, ATR and DNA-PK: Initiators of the cellular genotoxic stress responses. Carcinogenesis 24(10):1571-1580, 2003.
Yang J, Xu ZP, Huang Y, Hamrick HE, Duerksen-Hughes PJ. ATM and ATR: Sensing DNA damage. World J Gastroenterol. 10(2):155-160, 2004.
Yang J, Yu YI, Sun S and Duerksen-Hughes PJ. Ceramide and other sphingolipids in cellular responses. Cell Biochemistry and Biophysics 40:323-350, 2004.
Filippova M, Parkhurst L and Duerksen-Hughes PJ. The human papillomavirus 16 E6 protein binds to FADD and protects cells from Fas-triggered apoptosis. J. Biol. Chem. 29:25729-25744, 2004.
Filippova M, Brown-Bryan TA, Casiano CA and Duerksen-Hughes PJ. The human papillomavirus 16 E6 can render cells either sensitive or resistant to TNF: Effect of dose. Cell Death and Differentiation 12:1622-1635, 2005.
Garnett TO, Filippova M and Duerksen-Hughes PJ. Accelerated degradation of FADD and procaspase 8 in cells expressing human papillomavirus 16 E6 impairs TRAIL-mediated apoptosis. Cell Death and Differentiation 13:1915-1926, 2006.
Garnett, TO and Duerksen-Hughes PJ. Modulation of apoptosis by Human Papillomavirus (HPV) oncoproteins. Archives of Virology, 151:2321-2335, 2006.
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Last Revised: Wed, Nov 15, 2006