NOXA contributes to the sensitivity of PERK-deficient cells to ER stress.
PKR-like ER kinase (PERK) deficient mouse embryonic fibroblasts (MEFs) are hypersensitive to ER stress-induced apoptosis. However, the molecular determinants of increased sensitivity of PERK(-/-) MEFs are not clearly understood. Here we show that induction of several Unfolded Protein Response (UPR) target genes is attenuated in PERK(-/-) MEFs. We also report elevated expression of the BH3-only protein, NOXA in PERK(-/-) MEFs. Further, shRNA-mediated knockdown of NOXA rescued the hypersensitivity of PERK(-/-) MEFs to ER stress-induced apoptosis. Taken together our results suggest that compromised induction of UPR and increased NOXA expression contributes to hypersensitivity of PERK(-/-) MEFs to ER stress-induced apoptosis.
Apoptosis Research Centre, NUI Galway, Ireland.
Sanjeev
S
Gupta
Zoltan
Z
Giricz
Alessandro
A
Natoni
Neysan
N
Donnelly
Shane
S
Deegan
Eva
E
Szegezdi
Afshin
A
Samali
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D015870:Gene Expression; D051379:Mice; D018345:Mice, Knockout; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019284:Thapsigargin / Q000494:pharmacology; D014415:Tunicamycin / Q000494:pharmacology; D056811:Unfolded Protein Response / Q000235:genetics; D019892:eIF-2 Kinase / Q000172:deficiency / Q000235:genetics*
D020169:Caspases; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D019284:Thapsigargin; D014415:Tunicamycin; D019892:eIF-2 Kinase; C408009:Pmaip1 protein, mouse