Targeting phosphorylation of eukaryotic initiation factor-2α to treat human disease.
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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.
Proteasome Endopeptidase Complex
Eukaryotic Initiation Factor-2
Protein Processing, Post-Translational
Gene Knock-In Techniques
Unfolded Protein Response
Molecular Targeted Therapy
Endoplasmic Reticulum Stress
Published Version (Please cite this version)10.1016/b978-0-12-396456-4.00005-5
Publication InfoFullwood, Melissa J; Shenolikar, Shirish; & Zhou, Wei (2012). Targeting phosphorylation of eukaryotic initiation factor-2α to treat human disease. Progress in molecular biology and translational science, 106. pp. 75-106. 10.1016/b978-0-12-396456-4.00005-5. Retrieved from https://hdl.handle.net/10161/17238.
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Professor Emeritus of Psychiatry and Behavioral Sciences
Protein phosphorylation controls a wide range of physiological processes in mammalian tissues. Phosphorylation state of cellular proteins is controlled by the opposing actions of protein kinases and phosphatases that are regulated by hormones, neurotransmitters, growth factors and other environmental cues. Our research attempts to understand the communication between protein kinases and phosphatases that dictates cellular protein phosphorylation and the cell's response to hormones. Over the