|Penelope Duerksen-Hughes, PhD|
|Professor, Biochemistry and Microbiology|
|School of Medicine|
|University Faculty Profile|
Cervical cancer is the most common cancer for women worldwide, with a mortality rate of approximately 50 percent. This disease is almost always caused by high-risk strains of the human papillomavirus, a sexually transmitted agent, and disproportionately affects minority populations. HPV codes for E6 and E7, two oncogenes that work together to transform cells and cause cancer. Funded by an R01 award from the NIH, the Duerksen-Hughes laboratory has discovered that one of the ways in which E6 contributes to HPV oncogenicity is by helping the virus to evade the host immune response.
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. We are currently working to further define the roles played by these two splice variants.
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.
1. Tungteakkhun, S. S., M. Filippova, N. Fodor and P. J. Duerksen-Hughes. The Full Length Isoform of HPV 16 E6 and its Splice Variant E6* Bind to Different Sites on Procaspase 8 DED. J. Virol. 84:1453-1463, 2010.
2. Filippova, M., V. A. Filippov, M. Kagoda, T. Garnett, N. Fodor and P. J. Duerksen-Hughes. Complexes of Human Papillomavirus 16 E6 Proteins Form Pseudo-DISC Structures During TNF-Medicated Apoptosis. J. Virol. 83:210-227, 2009.
3. Tungteakkhun, S., M. Filippova, J. W. Neidigh, N. Fodor and P. J. Duerksen-Hughes. The Interaction Between HPV 16 E6 and FADD is Mediated by a Novel E6 Binding Domain. J. Virol. 82:9600-9614, 2008.
4. Filippov, V., E. L. Schmidt, M. Filippova and P. J. Duerksen-Hughes. Splicing and splice factor SRp55 participate in the response to DNA damage by changing isoform ratios of target genes. Gene. 420:34-41, 2008.
5. Haynes, T.-A S., P. J. Duerksen-Hughes, M. Filippova, V. Filippov and K. Zhang. C(18) Ceramide Analysis in Mammalian Cells Employing Reversed-Phase High Performance Liquid Chromatography Tandem Mass Spectrometry. Analytical Biochemistry. 378:80-86, 2008.
6. Filippov, V., M. Filippova and P. J. Duerksen-Hughes. The Early Response to DNA Damage Can Lead to Activation of Alternative Splicing Activity Resulting in CD44 Splice Pattern Changes. Cancer Research. 67:7621-7630, 2007.
7. Garnett, T. O., M. Filippova and P. J. Duerksen-Hughes. Bid is Cleaved Upstream of Caspase-8 Activation During TRAIL-Mediated Apoptosis in Human Osteosarcoma Cells. Apoptosis. 12:1299-1315, 2007.
8. Filippova, M., M. M. Johnson, M. Bautista, V. Filippov, N. Fodor, S. S. Tungteakkhun, K. Williams and P. J. Duerksen-Hughes. The Large and Small Isoforms of HPV 16 E6 Bind to and Differentially Affect Procaspase 8 Stability and Activity. J. Virology. 81:4116-4129, 2007.
9. Garnett, TO and Duerksen-Hughes PJ. Modulation of apoptosis by Human Papillomavirus (HPV) oncoproteins. Archives of Virology 151:2321-2335, 2006.
10. 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.
11. 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.
12. 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.
13. 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.
14. Filippova M, Duerksen-Hughes PJ . Inorganic and dimethylated arsenic species induce cellular p53. Chemical Research in Toxicology 16:423-431, 2003.
15. 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.
16. 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.