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Human papillomavirus type 16 E6 activates NF-kappaB, induces cIAP-2 expression, and protects against apoptosis in a PDZ binding motif-dependent manner. J Virol 2006 Jun;80(11):5301-7 PMID: 16699010 PMCID: PMC1472131

Pubmed ID

16699010

Abstract

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.

Author List

James MA, Lee JH, Klingelhutz AJ

Author

Michael James PhD Assistant Professor in the Surgery department at Medical College of Wisconsin




Scopus

2-s2.0-33646727381   99 Citations

MESH terms used to index this publication - Major topics in bold

Adaptor Proteins, Signal Transducing
Amino Acid Motifs
Apoptosis
Baculoviral IAP Repeat-Containing 3 Protein
Binding Sites
Epithelial Cells
Human papillomavirus 16
Humans
Inhibitor of Apoptosis Proteins
NF-kappa B
Ubiquitin-Protein Ligases
jenkins-FCD Prod-353 9ccd8489072cb19f5b9f808bb23ed672c582f41e