Chk1 inhibition activates p53 through p38 MAPK in tetraploid cancer cells Academic Article uri icon

Overview

MeSH Major

  • Protein Kinase Inhibitors
  • Protein Kinases
  • Tumor Suppressor Protein p53
  • p38 Mitogen-Activated Protein Kinases

abstract

  • We have previously shown that tetraploid cancer cells succumb through a p53-dependent apoptotic pathway when checkpoint kinase 1 (Chk1) is depleted by small interfering RNAs (siRNAs) or inhibited with 7-hydroxystaurosporine (UCN-01). Here, we demonstrate that Chk1 inhibition results in the activating phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK). Depletion of p38 MAPK by transfection with a siRNA targeting the alpha isoform of p38 MAPK (p38alpha MAPK) abolishes the phosphorylation of p53 on serines 15 and 46 that is induced by Chk1 knockdown. The siRNA-mediated downregulation and pharmacological inhibition of p38alpha MAPK (with SB 203580) also reduces cell death induced by Chk1 knockdown or UCN-01. These results underscore the role of p38 MAPK as a pro-apoptotic kinase in the p53-dependant pathway for the therapeutic elimination of polyploidy cells.

publication date

  • July 2008

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed ID

  • 18642443

Additional Document Info

start page

  • 1956

end page

  • 61

volume

  • 7

number

  • 13