Impaired tissue growth is mediated by checkpoint kinase 1 (CHK1) in the integrated stress response.
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.
Malzer
Elke
E
Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research (CIMR), Wellcome Trust/MRC Building, Hills Road, Cambridge, CB2 0XY, UK.
Daly
Marie-Louise
ML
Moloney
Aileen
A
Sendall
Timothy J
TJ
Thomas
Sally E
SE
Ryder
Edward
E
Ryoo
Hyung Don
HD
Crowther
Damian C
DC
Lomas
David A
DA
Marciniak
Stefan J
SJ
D000818:Animals; D002453:Cell Cycle / Q000502:physiology; D049109:Cell Proliferation; D000071877:Checkpoint Kinase 1; D004249:DNA Damage; D004331:Drosophila melanogaster / Q000201:enzymology / Q000235:genetics / Q000254:growth & development; D004721:Endoplasmic Reticulum / Q000201:enzymology / Q000235:genetics / Q000502:physiology; D004789:Enzyme Activation; D005123:Eye / Q000254:growth & development; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D010641:Phenotype; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D057165:Proteostasis Deficiencies / Q000235:genetics / Q000378:metabolism; D013312:Stress, Physiological / Q000235:genetics / Q000502:physiology*; D020687:cdc25 Phosphatases / Q000378:metabolism; D019892:eIF-2 Kinase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism
D000071877:Checkpoint Kinase 1; D011494:Protein Kinases; D020687:cdc25 Phosphatases; D019892:eIF-2 Kinase; C000605867:CHEK1 protein, human