The ferredoxin reductase gene is regulated by the p53 family and sensitizes cells to oxidative stress-induced apoptosis

Gang Liu, Xinbin Chen

Research output: Contribution to journalArticle

140 Scopus citations

Abstract

The p53 tumor suppressor protein, a transcription factor, induces cell cycle arrest and apoptosis via the upregulation of downstream target genes. Ferredoxin Reductase (protein, FR; gene, FDXR) transfers electron from NADPH to cytochrome P450 via ferredoxin in mitochondria. Here, we identified FDXR as a target gene of the p53 family, that is, p53, p63, and p73. We found that FDXR can be induced by DNA damage in cells in a p53-dependent manner and by a mutated form of p53 that is competent in inducing apoptosis. In addition, we identified a p53 response element located within the FDXR promoter that is responsive to wild-type p53, p63α, p63γ, p73α, and p73β. Furthermore, we showed that p53, p63α and p73α directly bind to the p53 response element in vivo and promote the accessibility of the FDXR promoter by increasing the acetylation of histones H3 and H4. To determine the role of FR in p53 tumor suppression, we generated cell lines that express FR using a tetracycline-regulated promoter. We found that over-expression of FR in lung H1299, breast MCF7, and colorectal HCT116 carcinoma cells have no effect on cell proliferation. However, we showed that FR increases the sensibility of H1299 and HCT116 cells to 5-fluorouracil-, doxorubicin- and H2O2- mediated apoptosis. Our data support a model of feed-forward loop for p53 activity, that is, various cellular stresses, including reactive oxygen species (ROS), activate p53, which induces the expression of FDXR; and the FDXR gene product, FR, in turn sensitizes cells to ROS-mediated apoptosis.

Original languageEnglish (US)
Pages (from-to)7195-7204
Number of pages10
JournalOncogene
Volume21
Issue number47
DOIs
StatePublished - Oct 17 2002
Externally publishedYes

Keywords

  • Apoptosis
  • FDXR
  • p53
  • p63
  • p73
  • ROS

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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