Journal
JOURNAL OF CELL SCIENCE
Volume 123, Issue 17, Pages 2892-2900Publisher
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/jcs.070078
Keywords
CHK1; Cell cycle; Endoplasmic reticulum stress; PERK
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Funding
- MRC (UK)
- EPSRC
- Addenbrooke's Charitable Trust
- MRC [G0601840, G0500306, G0700990] Funding Source: UKRI
- Alzheimers Research UK [ART-PhD2006-5] Funding Source: researchfish
- Medical Research Council [G0500306, G0601840, G0700990] Funding Source: researchfish
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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 eIF2 alpha 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.
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