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 tumor necrosis factor-induced apoptosis by binding to the C-terminal end of tumor necrosis factor 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. Although E6 suppresses activation of both caspase 3 and caspase 8, it does not affect apoptotic signaling through the mitochondrial pathway. High risk strains of human papillomavirus (HPV), 1 such as HPV 16 and 18, cause most cases of human cervical carcinoma (reviewed in Ref. 1). HPV 16 codes for two oncogenes, E6 and E7. E7 is best known for its ability to bind to and inactivate the retinoblastoma protein, whereas E6 was initially recognized for its ability to bind to and mediate the rapid, ubiquitin-dependent degradation of the tumor suppressor p53 (2). Although this ability clearly contributes to its oncogenic potential, E6 has additional biological and transforming activities that appear to be independent of p53 (3-11). Mechanistically, these activities are a consequence of the interactions of E6 with cellular proteins, and results from many laboratories, including our own, provide evidence that E6 does, in fact, interact with a wide variety of cellular proteins involved in a number of cellular functions (reviewed in Ref. 12). Identified E6 partners include the following: proteins involved in the regulation of transcription and DNA replication, such as p300/CBP (13, 14), hMcm7 (16,17), E6TP1 (18), and ADA3 (19,20); proteins involved in apoptosis and immune evasion such as Bak (21), c-Myc (22), and TNF receptor 1 (TNF R1) (23); proteins involved with epithelial organization and differentiation such as paxillin (24), E6BP/ERC-55 (25), zyxin (26), HPV 6 and fibulin-1 (27); proteins involved in cell-cell adhesion, polarity, and proliferation control that contain a PDZ-binding motif such as hDLG (28, 29), hScrib (30), MAGI-1 (31, 32), MAGI-2, MAGI-3 (33), and MUPP1 (34); and proteins involved in DNA repair such as XRCC1 (35) and 6-O-methylguanine-DNA methyltransferase (36). However, with some exceptions, the mechanisms and the consequences of the interactions between E6 and its reported cellular partners on either the host or the virus life cycle are not well understood.In previous work, our laboratory found that E6 could protect cells from TNF (37) and that it does so by binding to the C-terminal end of TNF R1, thus blocking transmission of the apoptotic signal from TNF R1 through the TNF R1-associated death domain (TRADD) (23). These observations led us t...