Chk1 inhibition activates p53 through p38 MAPK in tetraploid cancer cells

Ilio Vitale, Laura Senovilla, Lorenzo Galluzzi, Alfredo Criollo, Sonia Vivet, Maria Castedo, Guido Kroemer

Research output: Contribution to journalArticlepeer-review

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 α isoform of p38 MAPK (p38α 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 p38α 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.

Original languageEnglish
Pages (from-to)1956-1961
Number of pages6
JournalCell Cycle
Volume7
Issue number13
Publication statusPublished - Jul 1 2008

Keywords

  • Apoptosis
  • Genomic instability
  • Mitosis
  • Polyploidy
  • Spindle assembly checkpoint

ASJC Scopus subject areas

  • Cell Biology
  • Biochemistry
  • Molecular Biology

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