Electrophilic prostaglandins and lipid aldehydes repress redox-sensitive transcription factors p53 and hypoxia-inducible factor by impairing the selenoprotein thioredoxin reductase

Philip J. Moos, Kornelia Edes, Pamela Cassidy, Edmond Massuda, F. A. Fitzpatrick

Research output: Contribution to journalArticle

128 Scopus citations

Abstract

Tumor suppressor p53 exhibits an enigmatic phenotype in cells exposed to electrophilic, cyclopentenone prostaglandins of the A and J series. Namely, cells harboring a wild-type p53 gene accumulate p53 protein that is conformationally and functionally impaired. This occurs via an unknown molecular mechanism. We report that electrophilic cyclopentenone prostaglandins covalently modify and inhibit thioredoxin reductase, a selenoprotein that governs p53 and other redox-sensitive transcription factors. This mechanism accounts fully for the unusual p53 phenotype in cells exposed to electrophilic prostaglandins. Based on this mechanism we derived, tested, and affirmed several predictions regarding the kinetics of p53 inactivation; the protective effects of selenium; the structure-activity relationships for inhibition of thioredoxin reductase and impairment of p53 by electrophilic lipids; the susceptibility of hypoxia-inducible factor to inactivation by electrophilic lipids; and the equivalence of chemical inactivation of p53 to deletion of a p53 allele. Chemical precepts dictate that other electrophilic agents should also inhibit thioredoxin reductase and impair its governance of redox-sensitive proteins. Our results provide a novel framework to understand how endogenous and exogenous electrophiles might participate in carcinogenesis; how selenoproteins and selenium might confer protection against cancer; how certain tumors might acquire their paradoxical p53 phenotype; and how chronic inflammation might heighten the risk for cancer.

Original languageEnglish (US)
Pages (from-to)745-750
Number of pages6
JournalJournal of Biological Chemistry
Volume278
Issue number2
DOIs
StatePublished - Jan 10 2003

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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