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Papers In Press, published online ahead of print April 8, 2004
Center for Molecular Biology and GeneTherapy, Loma Linda University, Loma Linda, CA 92354
Corresponding Author: pdhughes{at}som.llu.edu
High risk strains of human papillomavirus (HPV), such as HPV 16, cause human cervical carcinoma. The E6 protein of HPV 16 mediates the rapid degradation of the tumor suppressor p53, although this is not the only function of E6 and cannot completely explain its transforming potential. Previous work in our laboratory has demonstrated that E6 can protect cells from TNF-induced apoptosis by binding to the C-terminal end of TNF R1, thus blocking apoptotic signal transduction. In this study, E6 was shown to also protect cells from apoptosis induced via the Fas pathway. Furthermore, use of an inducible E6-expression system demonstrated that this protection is dose-dependent, with higher levels of E6 leading to greater protection. While E6 suppresses activation of both caspase 3 and caspase 8, it does not affect apoptotic signaling through the mitochondrial pathway. Mammalian two-hybrid and in vitro pull-down assays were then used to demonstrate that E6 binds directly to the DED of FADD, with deletion and site-directed mutants enabling the localization of the E6 binding site to the N-terminal end of the FADD DED. E6 is produced in two forms: a full-length version of approximately 16 kD and a smaller version of about half that size corresponding to the N-terminal half of the full-length protein. Pull-down and functional assays demonstrated that the full-length, but not the small version of E6 was able to bind to FADD and to protect cells from Fas-induced apoptosis. In addition, binding to E6 leads to degradation of FADD, with the loss of cellular FADD proportional to the amount of E6 expressed. These results support a model in which E6-mediated degradation of FADD prevents transmission of apoptotic signals via the Fas pathway.
J. Biol. Chem, 10.1074/jbc.M401172200
Submitted on February 3, 2004
Revised on April 8, 2004
Accepted on April 8, 2004
The human Papillomavirus 16 E6 protein binds to FADD and protects cells from Fas-triggered apoptosis
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