title: Targeting phosphorylation of eukaryotic initiation factor-2α to treat human disease.
abstract: The unfolded protein response, also known as endoplasmic reticulum (ER) stress, has been implicated in numerous human diseases, including atherosclerosis, cancer, diabetes, and neurodegenerative disorders. Protein misfolding activates one or more of the three ER transmembrane sensors to initiate a complex network of signaling that transiently suppresses protein translation while also enhancing protein folding and proteasomal degradation of misfolded proteins to ensure full recovery from ER stress. Gene disruption studies in mice have provided critical insights into the role of specific signaling components and pathways in the differing responses of animal tissues to ER stress. These studies have emphasized an important contribution of translational repression to sustained insulin synthesis and β-cell viability in experimental models of type-2 diabetes. This has focused attention on the recently discovered small-molecule inhibitors of eIF2α phosphatases that prolong eIF2α phosphorylation to reduce cell death in several animal models of human disease. These compounds show significant cytoprotection in cellular and animal models of neurodegenerative disorders, highlighting a potential strategy for future development of drugs to treat human protein misfolding disorders.
authors.affiliation: Program in Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School Singapore, Singapore.
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Fullwood
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.forename: Shirish
authors.initials: S
authors.lastname: Shenolikar
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy* / Q000378:metabolism; D002934:Cinnamates / Q000494:pharmacology / Q000627:therapeutic use*; D003920:Diabetes Mellitus / Q000188:drug therapy* / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D005057:Eukaryotic Cells / Q000378:metabolism; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D055879:Gene Knock-In Techniques; D006143:Guanabenz / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008954:Models, Biological; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects; D017510:Protein Folding / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D056811:Unfolded Protein Response / Q000187:drug effects / Q000235:genetics
chemical_list: D002934:Cinnamates; D015852:Eukaryotic Initiation Factor-2; C496827:salubrinal; D010749:Phosphoprotein Phosphatases; D046988:Proteasome Endopeptidase Complex; D006143:Guanabenz; D013890:Thiourea