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First published online 12 February 2008
doi: 10.1242/jcs.013029

Journal of Cell Science 121, 664-674 (2008)
Published by The Company of Biologists 2008
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Research Article

Mechanisms underlying p53 regulation of PIK3CA transcription in ovarian surface epithelium and in ovarian cancer

Arezoo Astanehe1, David Arenillas2, Wyeth W. Wasserman2, Peter C. K. Leung1, Sandra E. Dunn3, Barry R. Davies4, Gordon B. Mills5 and Nelly Auersperg1,*

1 Department of Obstetrics and Gynecology
2 Centre for Molecular Medicine and Therapeutics
3 Laboratory for Oncogenomic Research, Department of Pediatrics, CFRI, University of British Columbia, Vancouver BC V6H3V5, Canada
4 AstraZeneca, Macclesfield, Cheshire, UK
5 Department of Molecular Therapeutics, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA

* Author for correspondence (e-mail: auersper{at}interchange.ubc.ca)

Accepted 1 December 2007

Inactivation of the transcription factor and tumor suppressor p53, and overexpression or mutational activation of PIK3CA, which encodes the p110{alpha} catalytic subunit of phosphatidylinositol-3-kinase (PI3K), are two of the most common deleterious genomic changes in cancer, including in ovarian carcinomas. We investigated molecular mechanisms underlying interactions between these two mediators and their possible roles in ovarian tumorigenesis. We identified two alternate PIK3CA promoters and showed direct binding of and transcriptional inhibition by p53 to one of these promoters. Conditional suppression of functional p53 increased p110{alpha} transcripts, protein levels and PI3K activity in immortalized, non-tumorigenic ovarian surface epithelial (OSE) cells, the precursors of ovarian carcinoma. Conversely, overexpression of p53 by adenoviral infection and activation of p53 by {gamma}-irradiation both diminished p110{alpha} protein levels in normal OSE and ovarian cancer cells. The demonstration that p53 binds directly to the PIK3CA promoter and inhibits its activity identifies a novel mechanism whereby these two mediators regulate cellular functions, and whereby inactivation of p53 and subsequent upregulation of PIK3CA might contribute to the pathophysiology of ovarian cancer.

Key words: PI3K, p53, PIK3CA promoter, Ovarian cancer, Ovarian surface epithelium






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