Transcriptional activation of caspase-6 and -7 genes by cisplatin-induced p53 and its functional significance in cisplatin nephrotoxicity.
This study examined the role of cisplatin-induced p53 activation in regulation of caspases and cellular injury during cisplatin nephrotoxicity. The executioner caspase-6 and -7 but not caspase-3 were identified as transcriptional targets of p53 in cisplatin injury as revealed by chromatin immunoprecipitation, a reporter gene and electrophoretic mobility shift assays, and real-time PCR following overexpression and inhibition of p53. DNA binding by p53 involved the first introns of the human and mouse caspase-7 gene and the mouse caspase-6 gene. Studies in human kidney, breast, ovary, colon, and prostate tumor cell lines also validated these findings. Treatment of p53 (-/-) cells with cisplatin did not induce caspase-6 and -7 expression and subsequent activation. In caspase-3 (-/-) cells, inhibition of caspase-6 and -7 activations markedly prevented cisplatin-induced cell death. In an in vivo model of cisplatin nephrotoxicity inhibition of p53 activation by a p53 inhibitor suppressed transactivation of the caspase-6 and -7 genes and prevented renal failure. p53 (-/-) mice were resistant to cisplatin nephrotoxicity as assessed by renal function and histology. These studies provide first evidence for p53-dependent transcriptional control of the caspase-6 and -7 genes and its functional significance in cisplatin injury to renal cells and functional implication of cisplatin-induced p53 induction in vitro and in vivo in cisplatin nephrotoxicity.
Yang
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John L McClellan Memorial Veterans Hospital, Central Arkansas Veterans Healthcare System and Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Kaushal
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V
Haun
R S
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Seth
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Shah
S V
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Kaushal
G P
GP
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis; D053178:Caspase 6 / Q000096:biosynthesis / Q000235:genetics*; D053179:Caspase 7 / Q000096:biosynthesis / Q000235:genetics*; D061945:Caspase Inhibitors; D020169:Caspases / Q000096:biosynthesis / Q000235:genetics; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002945:Cisplatin / Q000633:toxicity*; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D007684:Kidney Tubules / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000096:biosynthesis; D051437:Renal Insufficiency / Q000139:chemically induced; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D000970:Antineoplastic Agents; D061945:Caspase Inhibitors; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; C505514:CASP6 protein, human; C505520:CASP7 protein, human; C505516:Casp6 protein, mouse; C505524:Casp7 protein, mouse; D053178:Caspase 6; D053179:Caspase 7; D020169:Caspases; D002945:Cisplatin