Nuclear factor - kappaB-dependent regulation of p53 gene expression induced by daunomycin genotoxic drug.
Anthracycline drugs are widely used for the treatment of solid tumors and leukemia, but the molecular basis of their biological effect is still poorly understood. In the HCT116 colon carcinoma cell line, which retains a wild-type inducible p53 gene, we show that the anthracycline daunomycin is a potent inducer of p53 and NF-kappaB transcription factors. Nuclear accumulation of p53 protein occurred because of increased protein stability and enhanced gene expression. In addition, daunomycin induced the p53 promoter through the binding of p50/p65 NF-kappaB heterodimers to the kappaB site in the p53 promoter. Under our conditions, the free radical scavengers NAC and PDTC were not able to block NF-kappaB activation or p53 induction, indicating that reactive oxygen intermediates were not involved in the cellular response to daunomycin stimulation. Overexpression of a stable unresponsive IkappaBalpha mutant in HCT116 cells resulted in a complete inhibition of the NF-kappaB activation but only a partial impairment of the p53 protein accumulation induced by daunomycin. We conclude that the p53-activating signal generated by daunomycin is partially regulated by NF-kappaB.
Hellin
A C
AC
Laboratory of Medical Chemistry, University of Liège, Belgium.
Calmant
P
P
Gielen
J
J
Bours
V
V
Merville
M P
MP
D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D002467:Cell Nucleus / Q000378:metabolism; D015500:Chloramphenicol O-Acetyltransferase / Q000096:biosynthesis; D003110:Colonic Neoplasms; D003630:Daunorubicin / Q000633:toxicity*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000502:physiology; D016158:Genes, p53 / Q000187:drug effects; D006801:Humans; D008156:Luciferases / Q000096:biosynthesis; D016328:NF-kappa B / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis*
D000903:Antibiotics, Antineoplastic; D016328:NF-kappa B; D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53; D008156:Luciferases; D015500:Chloramphenicol O-Acetyltransferase; D003630:Daunorubicin