PERK and PKR: old kinases learn new tricks.
Regulating gene expression is an effective way for cells to deal with various stresses. The outcome of this regulation differs with the type of stress, and can promote either cell survival or cell death depending on the severity of the injury incurred. Gene expression can be controlled at several steps, including transcription, translation and degradation. An extensively studied protein involved in translational control is the eukaryotic translation initiation factor 2 (eIF2). When eIF2 becomes phosphorylated on a specific serine residue located within the alpha (alpha) subunit, global protein synthesis is halted. This phosphorylation occurs following periods of environmental stress, and plays a significant role in the cellular response to these events. The eIF2alpha kinase family consists of four members, which are each activated in response to different stimuli. Our group has recently discovered that two members of this family, the protein kinase activated by double-stranded RNA (PKR) and the PKR-like endoplasmic reticulum (ER) kinase (PERK) can also regulate the expression of specific proteins by promoting their degradation by the 26S proteasome. Specifically, we demonstrated that degradation of the cell cycle regulator cyclin D1, and the tumour suppressor p53 was promoted by PERK and PKR during periods of ER stress. This novel function may allow the eIF2alpha kinases to affect a larger number of cellular processes than previously believed.
Raven
Jennifer F
JF
Division of Experimental Medicine, Faculty of Medicine, McGill University and Lady Davis Institute for Medical Research, McGill University, Montreal, Quebec, Canada. jennifer.raven@mail.mcgill.ca
Koromilas
Antonis E
AE
D000818:Animals; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D014176:Protein Biosynthesis / Q000235:genetics*; D011506:Proteins / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism*
D019938:Cyclin D1; D015852:Eukaryotic Initiation Factor-2; D046988:Proteasome Endopeptidase Complex; D011506:Proteins; D016159:Tumor Suppressor Protein p53; D019892:eIF-2 Kinase; C061553:ATP dependent 26S protease