Keeping the eIF2 alpha kinase Gcn2 in check

Keeping the eIF2 alpha kinase Gcn2 in check

Author Castilho, Beatriz Amaral Autor UNIFESP Google Scholar
Shanmugam, Renuka Google Scholar
Silva, Richard Cardoso da Autor UNIFESP Google Scholar
Ramesh, Rashmi Google Scholar
Himme, Benjamin M. Google Scholar
Sattlegger, Evelyn Google Scholar
Institution Universidade Federal de São Paulo (UNIFESP)
Massey Univ
Abstract The protein kinase Gcn2 is present in virtually all eukaryotes and is of increasing interest due to its involvement in a large array of crucial biological processes. Some of these are universally conserved from yeast to humans, such as coping with nutrient starvation and oxidative stress. in mammals, Gcn2 is important for e.g. long-term memory formation, feeding behaviour and immune system regulation. Gcn2 has been also implicated in diseases such as cancer and Alzheimer's disease. Studies on Gcn2 have been conducted most extensively in Saccharomyces cerevisiae, where the mechanism of its activation by amino acid starvation has been revealed in most detail. Uncharged tRNAs stimulate Gcn2 which subsequently phosphorylates its substrate, eIF2 alpha, leading to reduced global protein synthesis and simultaneously to increased translation of specific mRNAs, e.g. those coding for Gcn4 in yeast and ATF4 in mammals. Both proteins are transcription factors that regulate the expression of a myriad of genes, thereby enabling the cell to initiate a survival response to the initial activating cue. Given that Gcn2 participates in many diverse processes, Gcn2 itself must be tightly controlled. Indeed, Gcn2 is regulated by a vast network of proteins and RNAs, the list of which is still growing. Deciphering molecular mechanisms underlying Gcn2 regulation by effectors and inhibitors is fundamental for understanding how the cell keeps Gcn2 in check ensuring normal organismal function, and how Gcn2-associated diseases may develop or may be treated. This review provides a critical evaluation of the current knowledge on mechanisms controlling Gcn2 activation or activity. (C) 2014 Published by Elsevier B.V.
Keywords Translational regulation
Uncharged tRNA
Language English
Sponsor Massey University Research Fund
Auckland Medical Research Foundation
Maurice & Phyllis Paykel Trust
Nutricia Research Foundation
Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
Massey University
Institute of Natural and Mathematical Sciences
Grant number Auckland Medical Research Foundation: 4109024
Auckland Medical Research Foundation: 4113010
Nutricia Research Foundation: 2010-35
FAPESP: 2009/52047-5
CNPq: 478903/2012-0
CNPq: 309860/2011-3
CNPq: 153660/2010-4
CAPES: 1915-13-4
Date 2014-09-01
Published in Biochimica Et Biophysica Acta-molecular Cell Research. Amsterdam: Elsevier B.V., v. 1843, n. 9, p. 1948-1968, 2014.
ISSN 0167-4889 (Sherpa/Romeo, impact factor)
Publisher Elsevier B.V.
Extent 1948-1968
Access rights Open access Open Access
Type Review
Web of Science ID WOS:000339535300016

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