Journal
BIOCHIMIE
Volume 95, Issue 11, Pages 1980-1990Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.biochi.2013.07.030
Keywords
eIF-2 alpha kinases; HRI; PKR; PERK; GCN2; Inhibitor; Activator
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Funding
- Department of Biotechnology (DBT), Government of India
- Ministry of Communications and Information Technology, Government of India
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Eukaryotic initiation factor 2 alpha kinases (eIF-2 alpha kinases) are key mediators of stress response in cells. In mammalian cells, there are four eIF-2 alpha kinases, namely HRI (Heme-Regulated Inhibitor), PKR (RNA-dependent Protein Kinase), PERK (PKR-like ER Kinase) and GCN2 (General Control Non-derepressible 2). These kinases get activated during diverse cytoplasmic stress conditions and phosphorylate the alpha-subunit of eIF2, leading to global protein synthesis inhibition. Therefore, eIF-2 alpha kinases play a vital role in various cellular processes such as proliferation, differentiation, apoptosis and cell signaling. Deregulation of eIF-2 alpha kinases and protein synthesis has been linked to numerous pathological conditions such as certain cancers, anemia and neurodegenerative disorders. Thus, modulation of these kinases by small molecules holds a great therapeutic promise. In this review we have compiled the available information on inhibitors and activators of these four eIF-2 alpha kinases. The review concludes with a note on the selectivity issue of currently available modulators and future perspectives for the design of specific small molecule probes. (C) 2013 Elsevier Masson SAS. All rights reserved.
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