This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Koivusalo, R. Articles by Hietanen, S. Search for Related Content PubMed PubMed Citation Articles by Koivusalo, R. Articles by Hietanen, S.

Activation of p53 in Cervical Cancer Cells by Human Papillomavirus E6 RNA Interference Is Transient, but Can Be Sustained by Inhibiting Endogenous Nuclear Export–Dependent p53 Antagonists

¹ The Joint Clinical Biochemistry Laboratory of University of Turku, Turku University Central Hospital and Wallac Oy; ² Medicity Research Laboratory and ³ Department of Medical Biochemistry and Molecular Biology, University of Turku; ⁴ Centre for Biotechnology, University of Turku and Åbo Akademi University; ⁵ Department of Obstetrics and Gynecology, Turku University Central Hospital, Turku, Finland; and ⁶ Institute of Medical Technology, University of Tampere and Tampere University Hospital, Tampere, Finland

Requests for reprints: Sakari Hietanen, Department of Obstetrics and Gynecology, Turku University Central Hospital, Kiinamyllynkatu 4-8, 20520 Turku, Finland. Phone: 358-2313-0200; Fax: 358-2313-2340; E-mail: sakari.hietanen{at}utu.fi.

p53 is degraded in cervical cancer cells by the human papillomavirus E6 and can be stabilized with short interfering RNA (siRNA) molecules targeting E6 mRNA. In this in vitro study, we show that E6 siRNA–induced p53 activation is transient in HeLa cervical cancer cells despite continuous suppression of E6 mRNA; activation can be sustained if the endogenous p53 antagonists COP1, MDM2, Pirh2, and c-Jun-NH₂-kinase are also targeted by siRNAs or by inhibiting the nuclear export of p53 with leptomycin B. The direct targeting of any one of these four cellular p53 antagonists had no effect on p53 activity when E6 was intact, but inhibited the fading off of E6 siRNA–induced p53 activation in nonstress conditions. The effect was additive when multiple cellular antagonists were concomitantly inhibited, indicating that all these proteins degrade p53 when E6 is inactivated. The antiproliferative effect induced by E6 silencing was enhanced when the endogenous p53 antagonists were additionally targeted. In conclusion, if human papillomavirus E6 is inhibited under nonstress conditions, the subsequent p53 activation is quickly reversed by the endogenous p53 degenerative machinery. The present results indicate that several cellular p53 antagonists must be inhibited for sustained p53 activity if E6 siRNA therapy is attempted and if no combined genotoxic therapy is applied. (Cancer Res 2006; 66(24): 11817-24)

This article has been cited by other articles:

				J. Barbier, M. Dutertre, D. Bittencourt, G. Sanchez, L. Gratadou, P. de la Grange, and D. Auboeuf Regulation of H-ras Splice Variant Expression by Cross Talk between the p53 and Nonsense-Mediated mRNA Decay Pathways Mol. Cell. Biol., October 15, 2007; 27(20): 7315 - 7333. [Abstract] [Full Text] [PDF]