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Published on: November 5, 2012

Impaired tissue growth is mediated by checkpoint kinase 1 (CHK1) in the integrated stress response

Elke Malzer1, Marie-Louise Daly, Aileen Moloney

  • 1Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research (CIMR), Wellcome Trust/MRC Building, Hills Road, Cambridge, CB2 0XY, UK.

Journal of Cell Science
|August 5, 2010
PubMed

Insights

The integrated stress response (ISR) links cell stress to cell cycle arrest via PERK and CHK1. This discovery reveals how cells halt proliferation during misfolded protein stress.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • The integrated stress response (ISR) is crucial for cellular protection against stress.
  • The ISR's role in solid tumor growth and its precise mechanisms influencing cellular proliferation remain incompletely understood.
  • A model for studying ISR signaling and its impact on tissue growth was needed.

Purpose of the Study:

  • To investigate the effects of ISR signaling on cellular proliferation and tissue growth.
  • To identify key molecular players mediating the ISR's influence on the cell cycle.

Main Methods:

  • Developed a model of ISR signaling using Drosophila melanogaster.
  • Utilized genetic screening of transposon insertions to identify relevant genes.
  • Employed RNA interference (RNAi) for gene knockdown.
  • Investigated checkpoint kinase 1 (CHK1) activation in mammalian cells.

Main Results:

  • Overexpression of the ISR kinase PERK in Drosophila caused an atrophic eye phenotype, rescued by GADD34.
  • A genetic screen identified 'grapes,' the Drosophila CHK1 orthologue.
  • Knockdown of grapes/CHK1 rescued eye development despite PERK activation.
  • PERK activation was necessary and sufficient for CHK1 activation and G2 cell cycle delay in mammalian cells.

Conclusions:

  • Non-genotoxic misfolded protein stress engages DNA-damage-induced cell cycle checkpoints.
  • The ISR couples cellular stress responses to cell cycle arrest through the PERK-CHK1 pathway.
  • This mechanism provides a link between protein misfolding, stress response, and proliferation control.

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