Malzer, E., Daly, M.L., Moloney, A., Sendall, T.J., Thomas, S.E., Ryder, E., Ryoo, H.D., Crowther, D.C., Lomas, D.A., Marciniak, S.J. (2010). Impaired tissue growth is mediated by checkpoint kinase 1 (CHK1) in the integrated stress response.  J. Cell Sci. 123(17): 2892--2900.

FBrf0211608

Research paper

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.

PMC2923568 (PMC) (EuropePMC)