Ferredoxin reductase affects p53-dependent, 5-fluorouracil-induced apoptosis in colorectal cancer cells

Paul M. Hwang, Fred Bunz, Jian Yu, Carlo Rago, Timothy A. Chan, Michael P. Murphy, Geoffry F. Kelso, Robin A.J. Smith, Kenneth W. Kinzler, Bert Vogelstein

Research output: Contribution to journalArticlepeer-review

Abstract

Loss of p53 gene function, which occurs in most colon cancer cells, has been shown to abolish the apoptotic response to 5-fluorouracil (5-FU). To identify genes downstream of p53 that might mediate these effects, we assessed global patterns of gene expression following 5-FU treatment of isogenic cells differing only in their p53 status. The gene encoding mitochondrial ferredoxin reductase (protein, FR; gene, FDXR) was one of the few genes significantly induced by p53 after 5-FU treatment. The FR protein was localized to mitochondria and suppressed the growth of colon cancer cells when over-expressed. Targeted disruption of the FDXR gene in human colon cancer cells showed that it was essential for viability, and partial disruption of the gene resulted in decreased sensitivity to 5-FU-induced apoptosis. These data, coupled with the effects of pharmacologic inhibitors of reactive oxygen species, indicate that FR contributes to p53-mediated apoptosis through the generation of oxidative stress in mitochondria.

Original languageEnglish (US)
Pages (from-to)1111-1117
Number of pages7
JournalNature medicine
Volume7
Issue number10
DOIs
StatePublished - 2001

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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