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

Cell Death Differ. 2008 Mar;15(3):530-44. doi: 10.1038/sj.cdd.4402287. Epub 2007 Dec 7.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / toxicity*
  • Apoptosis
  • Caspase 6 / biosynthesis
  • Caspase 6 / genetics*
  • Caspase 7 / biosynthesis
  • Caspase 7 / genetics*
  • Caspase Inhibitors
  • Caspases / biosynthesis
  • Caspases / genetics
  • Cell Line, Tumor
  • Cells, Cultured
  • Cisplatin / toxicity*
  • Humans
  • Kidney / drug effects
  • Kidney / enzymology
  • Kidney Tubules / cytology
  • Kidney Tubules / drug effects*
  • Kidney Tubules / metabolism
  • Mice
  • Mice, Knockout
  • RNA, Messenger / biosynthesis
  • Renal Insufficiency / chemically induced
  • Transcriptional Activation*
  • Tumor Suppressor Protein p53 / antagonists & inhibitors
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Antineoplastic Agents
  • Caspase Inhibitors
  • RNA, Messenger
  • Tumor Suppressor Protein p53
  • CASP6 protein, human
  • CASP7 protein, human
  • Casp6 protein, mouse
  • Casp7 protein, mouse
  • Caspase 6
  • Caspase 7
  • Caspases
  • Cisplatin