Functional inactivation of p73, a homolog of p53 tumor suppressor protein,by human papillomavirus E6 proteins

Citation
Js. Park et al., Functional inactivation of p73, a homolog of p53 tumor suppressor protein,by human papillomavirus E6 proteins, INT J CANC, 91(6), 2001, pp. 822-827
Citations number
26
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Onconogenesis & Cancer Research
Journal title
INTERNATIONAL JOURNAL OF CANCER
ISSN journal
0020-7136 → ACNP
Volume
91
Issue
6
Year of publication
2001
Pages
822 - 827
Database
ISI
SICI code
0020-7136(20010315)91:6<822:FIOPAH>2.0.ZU;2-D
Abstract
Human papillomavirus (HPV) is strongly implicated as a causative agent in t he etiology of cervical cancer. Of its gene products, E6 binds to and inact ivates p53 tumor suppressor protein by ubiquitin/proteasome-dependent degra dation. Recently, p73, a novel family of p53, has been identified and demon strated, like p53, to activate p21(WAFI). Here we show that p73 is also ina ctivated by HPV-E6, but ubiquitin-mediated proteolysis is not responsive. Y east two-hybrid and GST pull-down assays indicate a physical interaction be tween p73 and either HPV-16 or HPV-11 E6 proteins in vivo and in vitro, res pectively. The transactivation domain (amino acid residues to 49) is found to be absolutely required for the interaction. Transient co-expression of E 6 significantly inhibits the p73-mdiated activation of p21(WAFI) promoter i n a p53-defective C33A cell line. Using Ga14-p73 fusion protein, we demonst rate that E6 inhibition of p73 transactivation function is independent of s equence-specific DNA binding, which is confirmed by a direct electrophoreti c mobility shift assay. Moreover, E6 inhibits p73 function by interfering w ith the activity of the amino-terminal activation domain. Co-transfection o f E6 mutants reveals that the same portion of E6 appears to be responsible for the inactivation of p53 and p73 function. However, the inactivation mec hanism of p73 is clearly different from that of p53, because p73, unlike p5 3, is inactivated by both high- and low-risk E6s and is not susceptible to Eb-dependent proteolysis. These overall results, consequently, suggest that in addition to the inactivation of p53, the functional interference of p73 by HPV-E6 may, at least in part, contribute to Eb-mediated transformation and hyperproliferation of cervical cells. (C) 2001 Wiley-Liss, Inc.