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

Arezoo Astanehe, David Arenillas, Wyeth W. Wasserman, Peter C.K. Leung, Sandra E. Dunn, Barry R. Davies, Gordon B. Mills, Nelly Auersperg

Research output: Contribution to journalArticlepeer-review

64 Scopus citations

Abstract

Inactivation of the transcription factor and tumor suppressor p53, and overexpression or mutational activation of PIK3CA, which encodes the p110α catalytic subunit of phosphatidylinositol-3-kinase (P13K), 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 p110α transcripts, protein levels and P13K 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 γ-irradiation both diminished p110α 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.

Original languageEnglish (US)
Pages (from-to)664-674
Number of pages11
JournalJournal of Cell Science
Volume121
Issue number5
DOIs
StatePublished - Mar 1 2008
Externally publishedYes

Keywords

  • Ovarian cancer
  • Ovarian surface epithelium
  • P53
  • PI3K
  • PIK3CA promoter

ASJC Scopus subject areas

  • Cell Biology

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