Redox regulation of p53 during hypoxia

Navdeep S. Chandel*, Matthew G. Vander Heiden, Craig B. Thompson, Paul T. Schumacker

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

134 Scopus citations

Abstract

The transcription factor p53 can induce growth arrest or death in cells. Tumor cells that develop mutations in p53 demonstrate a diminished apoptotic potential, which may contribute to growth and tumor metastasis. Cellular levels of p53 are stabilized during hypoxia. The present study tested the hypothesis that reactive oxygen species (ROS) released from mitochondria regulate the cytosolic redox state and are required for the stabilization of p53 protein levels in response to hypoxia. Our results indicate that hypoxia (1.5% O2) increases mitochondrial ROS generation and increases p53 protein levels in human breast carcinoma MCF-7 cells and in normal human diploid fibroblast IMR-90 cells. MCF-7 cells depleted of their mitochondrial DNA (ρ° cells) failed to stabilize p53 protein levels during hypoxia. The antioxidant N-acetylcysteine and the Cu/Zn superoxide dismutase inhibitor diethyldithiocarbamic acid abolished the hypoxia-induced increases in ROS and p53 levels. Rotenone, an inhibitor of mitochondrial complex I, and 4,4-diisothiocyanato-stilbene-2,2'-disulfonate, a mitochondrial anion channel inhibitor, also abolished the increase in ROS signal and p53 levels during hypoxia. The p53-dependent gene p21(WAF1/CIP1) was also induced by hypoxia in both MCF-7 and IMR-90 cells without affecting the growth rate of either cell line. In contrast, both cell lines exhibited increases in p21(WAF1/CIP1) expression and growth arrest after gamma irradiation. Primary chick cardiac myocytes and routine embryonic fibroblasts also showed an increase in p53 protein levels in response to hypoxia without cell death or growth arrest. These results indicate that mitochondria regulate p53 protein levels during hypoxia through a redox-dependent mechanism involving ROS. Despite p53-induction, hypoxia alone does not cause either growth arrest or cell death.

Original languageEnglish (US)
Pages (from-to)3840-3848
Number of pages9
JournalOncogene
Volume19
Issue number34
DOIs
StatePublished - Aug 10 2000

Keywords

  • Apoptosis
  • Cell cycle
  • Hydrogen peroxide
  • Mitochondria
  • Reactive oxygen species

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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