The double-strand RNA-dependent protein kinase PKR plays a significant role in a sustained ER stress-induced apoptosis.
Sustained ER stress leads to apoptosis. However, the exact mechanism still remains to be elucidated. Here, we demonstrate that the double strand RNA-dependent protein kinase (PKR) is involved in the ER stress-mediated signaling pathway. ER stress rapidly activated PKR, inducing the phosphorylation of eIF2alpha, followed by the activation of the ATF4/CHOP pathway. ER-stress-mediated eIF2alpha/ATF4/CHOP signaling and associated cell death was markedly reduced by PKR knockdown. We also found that PKR activation was mediated by PACT, the expression of which was elevated by ER-stress. These results indicate that the ER-stress-mediated eIF2alpha/ATF4/CHOP/cell death pathway is, to some degree, dependent on PACT-mediated PKR activation apart from the PERK pathway.
Lee
Eun-Soo
ES
Department of Biological Science, Sungkyunkwan University, Cheoncheon-dong 300, Jangan-gu, Suwon, Gyeonggi-do 440-746, South Korea.
Yoon
Cheol-Hee
CH
Kim
Yeon-Soo
YS
Bae
Yong-Soo
YS
D051701:Activating Transcription Factor 4 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D008954:Models, Biological; D014176:Protein Biosynthesis / Q000187:drug effects; D016601:RNA-Binding Proteins / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects; D019284:Thapsigargin / Q000494:pharmacology; D051742:Transcription Factor CHOP / Q000378:metabolism; D019892:eIF-2 Kinase / Q000378:metabolism*
D051701:Activating Transcription Factor 4; D016601:RNA-Binding Proteins; D019284:Thapsigargin; D051742:Transcription Factor CHOP; D019892:eIF-2 Kinase; C497109:ATF4 protein, human; C104647:PRKRA protein, human