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

J Cell Sci. 2010 Sep 1;123(Pt 17):2892-900. doi: 10.1242/jcs.070078. Epub 2010 Aug 3.

Abstract

The integrated stress response (ISR) protects cells from numerous forms of stress and is involved in the growth of solid tumours; however, it is unclear how the ISR acts on cellular proliferation. We have developed a model of ISR signalling with which to study its effects on tissue growth. Overexpression of the ISR kinase PERK resulted in a striking atrophic eye phenotype in Drosophila melanogaster that could be rescued by co-expressing the eIF2alpha phosphatase GADD34. A genetic screen of 3000 transposon insertions identified grapes, the gene that encodes the Drosophila orthologue of checkpoint kinase 1 (CHK1). Knockdown of grapes by RNAi rescued eye development despite ongoing PERK activation. In mammalian cells, CHK1 was activated by agents that induce ER stress, which resulted in a G2 cell cycle delay. PERK was both necessary and sufficient for CHK1 activation. These findings indicate that non-genotoxic misfolded protein stress accesses DNA-damage-induced cell cycle checkpoints to couple the ISR to cell cycle arrest.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle / physiology
  • Cell Proliferation
  • Checkpoint Kinase 1
  • DNA Damage
  • Drosophila melanogaster / enzymology
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / growth & development
  • Endoplasmic Reticulum / enzymology
  • Endoplasmic Reticulum / genetics
  • Endoplasmic Reticulum / physiology
  • Enzyme Activation
  • Eye / growth & development
  • Female
  • Gene Knockdown Techniques
  • Humans
  • Male
  • Phenotype
  • Protein Kinases / genetics
  • Protein Kinases / metabolism
  • Protein Kinases / physiology*
  • Proteostasis Deficiencies / genetics
  • Proteostasis Deficiencies / metabolism
  • Stress, Physiological / genetics
  • Stress, Physiological / physiology*
  • cdc25 Phosphatases / metabolism
  • eIF-2 Kinase / biosynthesis
  • eIF-2 Kinase / genetics
  • eIF-2 Kinase / metabolism

Substances

  • Protein Kinases
  • CHEK1 protein, human
  • Checkpoint Kinase 1
  • PERK kinase
  • eIF-2 Kinase
  • cdc25 Phosphatases