PERK-dependent regulation of IAP translation during ER stress.
Exposure of cells to endoplasmic reticulum (ER) stress leads to activation of phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway and transcriptional induction of the inhibitor of apoptosis family of proteins. One of the proximal effectors of the ER stress response, the PKR-like ER kinase (PERK), leads to cellular adaptation to stress by multiple mechanisms, including attenuation of protein synthesis and transcriptional induction of pro-survival genes. Although PERK activity leads to cellular adaptation to ER stress, we now demonstrate that PERK activity also inhibits the ER stress-induced apoptotic program through the induction of cellular inhibitor of apoptosis (cIAP1 and cIAP2) proteins. This induction of IAPs occurs through both transcriptional and translational responses that are PERK dependent. Reintroduction of cIAP1 or cIAP2 expression into PERK-/- murine embryonic fibroblasts during ER stress delays the early onset of ER stress-induced caspase activation and apoptosis observed in these cells. Furthermore, we demonstrate that the activation of the PI3K-Akt pathway by ER stress is dependent on PERK, suggesting additional ways in which PERK activity protects cells from ER stress-induced apoptosis.
Hamanaka
R B
RB
Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA, USA.
Bobrovnikova-Marjon
E
E
Ji
X
X
Liebhaber
S A
SA
Diehl
J A
JA
D000818:Animals; D017209:Apoptosis; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D041681:NIH 3T3 Cells; D011132:Polyribosomes / Q000378:metabolism; D014176:Protein Biosynthesis; D014158:Transcription, Genetic; D044767:Ubiquitin-Protein Ligases; D019892:eIF-2 Kinase / Q000378:metabolism*
D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D051034:Inhibitor of Apoptosis Proteins; D044767:Ubiquitin-Protein Ligases; D019892:eIF-2 Kinase; C494833:BIRC2 protein, human; C494832:BIRC3 protein, human