Cisplatin induces apoptosis through the ERK-p66shc pathway in renal proximal tubule cells

Cancer Lett. 2010 Nov 28;297(2):165-70. doi: 10.1016/j.canlet.2010.05.007. Epub 2010 Jun 12.

Abstract

The extracellular signal-regulated kinase (ERK) has been shown to mediate cisplatin (CP)-induced toxicity to renal proximal tubule cells. Here, we demonstrate that ERK serves as the kinase that phosphorylates the pro-apoptotic p66shc protein at its Serine36 residue in CP-treated renal proximal tubule cells. Pharmacologic or dominant-negative inhibition of ERK mitigates cisplatin-induced Ser36 phosphorylation of p66shc. Overexpression of p66shc exacerbates while its knockdown or mutation of the Serine36 site to alanine ameliorates CP-induced nephrotoxicity in vitro. Since p66shc is Serine36 phosphorylated in the kidneys of mice after treatment with CP, a similar mechanism might exist in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cisplatin / pharmacology*
  • Cisplatin / toxicity
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Kidney Diseases / chemically induced*
  • Kidney Diseases / enzymology
  • Kidney Diseases / metabolism
  • Kidney Diseases / pathology
  • Kidney Tubules, Proximal / drug effects*
  • Kidney Tubules, Proximal / enzymology
  • Kidney Tubules, Proximal / metabolism
  • Kidney Tubules, Proximal / pathology
  • Male
  • Mice
  • Phosphorylation
  • Shc Signaling Adaptor Proteins / metabolism*
  • Src Homology 2 Domain-Containing, Transforming Protein 1

Substances

  • Shc Signaling Adaptor Proteins
  • Shc1 protein, mouse
  • Src Homology 2 Domain-Containing, Transforming Protein 1
  • Extracellular Signal-Regulated MAP Kinases
  • Cisplatin