The causative agents in the majority of cervical cancers and more than half of all other anogenital cancers are the high-risk strains of the human papillomavirus (HPV) such as HPV-16 and HPV-18, and the primary mediators of this malignant transformation are the two oncoproteins, E6 and E7. It is well known that E6 binds to and degrades the p53 tumor suppressor protein. However, this is not its only activity. Our lab has shown that E6 also binds to TNF R1 and to FADD, and can protect cells from apoptosis induced by both TNF and FasL. TRAIL is a recently discovered member of the TNF super family and most closely resembles FasL. It is therefore quite likely that E6 may also modulate cellular responses to TRAIL as do other viral proteins such as E5 and HIV tat. One reason is that E6 degrades FADD, and FADD is thought to function as a key component of the TRAIL DISC in at least some cell types. The proposed project will address the following questions: 1) Does E6 protect cells from TRAIL-mediated apoptosis? 2) Does the pattern of TRAIL receptor expression play a role in the ability of E6 to protect cells from TRAIL-mediated apoptosis? 3) What is the mechanism underlying this protection? 4) Can the inhibition of TRAIL-induced apoptosis by E6 be abrogated? These studies are significant because an enhanced understanding of viral/host interactions is critical to the development of novel and improved therapies. One of the strategies employed by HPV's to escape immunological surveillance during the progression of cervical cancer is to interfere with apoptosis and E6 seems to function as a key player in this respect. In addition, TRAIL is thought to selectively target transformed and virus infected cells and is currently being tested in clinical trials. The present study will contribute to our understanding of virus/host interactions and more specifically the strategies used by viruses to undermine host defenses.
| Garnett, Theodore O; Filippova, Maria; Duerksen-Hughes, Penelope Jayne (2007) Bid is cleaved upstream of caspase-8 activation during TRAIL-mediated apoptosis in human osteosarcoma cells. Apoptosis 12:1299-315 |
| Garnett, T O; Filippova, M; Duerksen-Hughes, P J (2006) Accelerated degradation of FADD and procaspase 8 in cells expressing human papilloma virus 16 E6 impairs TRAIL-mediated apoptosis. Cell Death Differ 13:1915-26 |
