title: Ferredoxin reductase affects p53-dependent, 5-fluorouracil-induced apoptosis in colorectal cancer cells.
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.
authors.affiliation: Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: P M
authors.initials: PM
authors.lastname: Hwang
authors.forename: F
authors.initials: F
authors.lastname: Bunz
authors.forename: J
authors.initials: J
authors.lastname: Yu
authors.forename: C
authors.initials: C
authors.lastname: Rago
authors.forename: T A
authors.initials: TA
authors.lastname: Chan
authors.forename: M P
authors.initials: MP
authors.lastname: Murphy
authors.forename: G F
authors.initials: GF
authors.lastname: Kelso
authors.forename: R A
authors.initials: RA
authors.lastname: Smith
authors.forename: K W
authors.initials: KW
authors.lastname: Kinzler
authors.forename: B
authors.initials: B
authors.lastname: Vogelstein
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis; D002455:Cell Division / Q000187:drug effects; D015179:Colorectal Neoplasms; D005287:Ferredoxin-NADP Reductase / Q000235:genetics / Q000502:physiology*; D005434:Flow Cytometry; D005472:Fluorouracil / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D018390:Gene Targeting / Q000379:methods; D006801:Humans; D018384:Oxidative Stress; D011995:Recombination, Genetic; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000964:Antimetabolites, Antineoplastic; D016159:Tumor Suppressor Protein p53; D005287:Ferredoxin-NADP Reductase; D005472:Fluorouracil