期刊
NATURE MEDICINE
卷 7, 期 10, 页码 1111-1117出版社
NATURE AMERICA INC
DOI: 10.1038/nm1001-1111
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资金
- NCI NIH HHS [R37 CA043460, CA 43460] Funding Source: Medline
- NIGMS NIH HHS [GM 07184, T32 GM007184] Funding Source: Medline
Loss of p53 gene function, which occurs in most colon cancer cells, has been shown to abolish the apoptotic response to 5-fluorouracil (54U). 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 FIR contributes to p53-mediated apoptosis through the generation of oxidative stress in mitochondria.
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