Ubiquitin-independent degradation of p53 mediated by high-risk human papillomavirus protein E6

• Published in: Oncogene Vol. 26; no. 28; pp. 4059 - 4070
• Main Authors: CAMUS, S, MENENDEZ, S, CHEOK, C. F, STEVENSON, L. F, LAIN, S, LANE, D. P
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 14.06.2007; Nature Publishing Group
• Subjects: Animals; Biological and medical sciences; Cell Line; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cellular biology; Degradation; Fundamental and applied biological sciences. Psychology; Genetic aspects; Health aspects; Human papillomavirus; Hydrolysis; MDM2 protein; Mice; Molecular and cellular biology; Molecular biology; Oncology; p53 Protein; Papillomaviridae - metabolism; Papillomavirus infections; Proteasome 26S; Proteins; Tumor suppressor genes; Tumor Suppressor Protein p53 - metabolism; Ubiquitin; Ubiquitin - metabolism; Ubiquitin-proteasome system; Ubiquitin-protein ligase; Ubiquitination; Viral Proteins - metabolism; Singapore; Ubiquitin; Multicatalytic endopeptidase complex; High risk; proteasome; Enzyme; degradation; Papovaviridae; Carcinogenesis; Protein; p53; Papillomavirus; Virus; Peptidases; E6; Human papillomavirus; TP53 Gene; ubiquitination; Hydrolases; Tumor suppressor gene
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1210188

In vitro, high-risk human papillomavirus E6 proteins have been shown, in conjunction with E6-associated protein (E6AP), to mediate ubiquitination of p53 and its degradation by the 26S proteasome by a pathway that is thought to be analogous to Mdm2-mediated p53 degradation. However, differences in the requirements of E6/E6AP and Mdm2 to promote the degradation of p53, both in vivo and in vitro, suggest that these two E3 ligases may promote p53 degradation by distinct pathways. Using tools that disrupt ubiquitination and degradation, clear differences between E6- and Mdm2-mediated p53 degradation are presented. The consistent failure to fully protect p53 protein from E6-mediated degradation by disrupting the ubiquitin-degradation pathway provides the first evidence of an E6-dependent, ubiquitin-independent, p53 degradation pathway in vivo.