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Cell Death Differ. 2008 Mar;15(3):530-44. Epub 2007 Dec 7.

Transcriptional activation of caspase-6 and -7 genes by cisplatin-induced p53 and its functional significance in cisplatin nephrotoxicity.

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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.


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.

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