Human papillomavirus type 16 E6 activates NF-kappaB, induces cIAP-2 expression, and protects against apoptosis in a PDZ binding motif-dependent manner.
Infection with human papillomavirus (HPV) is a critical factor in the pathogenesis of most cervical cancers and some aerodigestive cancers. The HPV E6 oncoprotein from high-risk HPV types contributes to the immortalization and transformation of cells by multiple mechanisms, including degradation of p53, transcriptional activation of human telomerase reverse transcriptase (hTERT), and degradation of several proteins containing PDZ domains. The ability of E6 to bind PDZ domain-containing proteins is independent of p53 degradation or hTERT activation but does correlate with oncogenic potential (R. A. Watson, M. Thomas, L. Banks, and S. Roberts, J. Cell Sci. 116:4925-4934, 2003) and is essential for induction of epithelial hyperplasia in vivo (M. L. Nguyen, M. M. Nguyen, D. Lee, A. E. Griep, and P. F. Lambert, J. Virol. 77:6957-6964, 2003). In this study, we found that HPV type 16 E6 was able to activate NF-kappaB in airway epithelial cells through the induction of nuclear binding activity of p52-containing NF-kappaB complexes in a PDZ binding motif-dependent manner. Transcript accumulation for the NF-kappaB-responsive antiapoptotic gene encoding cIAP-2 and binding of nuclear factors to the proximal NF-kappaB binding site of the cIAP-2 gene promoter are induced by E6 expression. Furthermore, E6 is able to protect cells from TNF-induced apoptosis. All of these E6-dependent phenotypes are dependent on the presence of the PDZ binding motif of E6. Our results imply a role for targeting of PDZ proteins by E6 in NF-kappaB activation and protection from apoptosis in airway epithelial cells.
James
Michael A
MA
Department of Microbiology, and Holden Cancer Center, University of Iowa, Iowa City, IA 52242, USA.
Lee
John H
JH
Klingelhutz
Aloysius J
AJ
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D020816:Amino Acid Motifs / Q000502:physiology; D017209:Apoptosis / Q000502:physiology*; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D001665:Binding Sites; D004847:Epithelial Cells / Q000821:virology; D052162:Human papillomavirus 16 / Q000502:physiology*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases
D048868:Adaptor Proteins, Signal Transducing; D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; C494832:BIRC3 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D044767:Ubiquitin-Protein Ligases