title: Perk is essential for translational regulation and cell survival during the unfolded protein response.
abstract: Malfolded proteins in the endoplasmic reticulum (ER) inhibit translation initiation. This response is believed to be mediated by increased phosphorylation of eukaryotic initiation factor 2alpha (eIF2alpha) and is hypothesized to reduce the work load imposed on the folding machinery during stress. Here we report that mutating the gene encoding the ER stress-activated eIF2alpha kinase PERK abolishes the phosphorylation of eIF2alpha in response to accumulation of malfolded proteins in the ER resulting in abnormally elevated protein synthesis and higher levels of ER stress. Mutant cells are markedly impaired in their ability to survive ER stress and inhibition of protein synthesis by cycloheximide treatment during ER stress ameliorates this impairment. PERK thus plays a major role in the ability of cells to adapt to ER stress.
authors.affiliation: Department of Medicine, The Kaplan Cancer Center, New York University School of Medicine, New York 10016, USA.
authors.forename: H P
authors.initials: HP
authors.lastname: Harding
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: A
authors.initials: A
authors.lastname: Bertolotti
authors.forename: H
authors.initials: H
authors.lastname: Zeng
authors.forename: D
authors.initials: D
authors.lastname: Ron
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D002470:Cell Survival; D003513:Cycloheximide / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D005786:Gene Expression Regulation; D051379:Mice; D009154:Mutation; D010766:Phosphorylation; D014176:Protein Biosynthesis / Q000187:drug effects; D017510:Protein Folding; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D014415:Tunicamycin / Q000494:pharmacology; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism*
chemical_list: D003513:Cycloheximide; D015852:Eukaryotic Initiation Factor-2; D011500:Protein Synthesis Inhibitors; D014415:Tunicamycin; D019892:eIF-2 Kinase