Ferredoxin reductase affects p53-dependent, 5-fluorouracil-induced apoptosis in colorectal cancer cells.
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.
Hwang
P M
PM
Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Bunz
F
F
Yu
J
J
Rago
C
C
Chan
T A
TA
Murphy
M P
MP
Kelso
G F
GF
Smith
R A
RA
Kinzler
K W
KW
Vogelstein
B
B
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*
D000964:Antimetabolites, Antineoplastic; D016159:Tumor Suppressor Protein p53; D005287:Ferredoxin-NADP Reductase; D005472:Fluorouracil