Keeping the eIF2 alpha kinase Gcn2 in check

dc.contributor.authorCastilho, Beatriz Amaral [UNIFESP]
dc.contributor.authorShanmugam, Renuka
dc.contributor.authorSilva, Richard Cardoso da [UNIFESP]
dc.contributor.authorRamesh, Rashmi
dc.contributor.authorHimme, Benjamin M.
dc.contributor.authorSattlegger, Evelyn
dc.contributor.institutionUniversidade Federal de São Paulo (UNIFESP)
dc.contributor.institutionMassey Univ
dc.description.abstractThe 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.en
dc.description.affiliationUniversidade Federal de São Paulo, Escola Paulista Med, Dept Microbiol Immunol & Parasitol, São Paulo, Brazil
dc.description.affiliationMassey Univ, Inst Nat & Math Sci, Auckland 0745, Albany, New Zealand
dc.description.affiliationUnifespUniversidade Federal de São Paulo, Escola Paulista Med, Dept Microbiol Immunol & Parasitol, São Paulo, Brazil
dc.description.sourceWeb of Science
dc.description.sponsorshipMassey University Research Fund
dc.description.sponsorshipAuckland Medical Research Foundation
dc.description.sponsorshipMaurice & Phyllis Paykel Trust
dc.description.sponsorshipNutricia Research Foundation
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.description.sponsorshipConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
dc.description.sponsorshipCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
dc.description.sponsorshipMassey University
dc.description.sponsorshipInstitute of Natural and Mathematical Sciences
dc.description.sponsorshipIDAuckland Medical Research Foundation: 4109024
dc.description.sponsorshipIDAuckland Medical Research Foundation: 4113010
dc.description.sponsorshipIDNutricia Research Foundation: 2010-35
dc.description.sponsorshipIDFAPESP: 2009/52047-5
dc.description.sponsorshipIDCNPq: 478903/2012-0
dc.description.sponsorshipIDCNPq: 309860/2011-3
dc.description.sponsorshipIDCNPq: 153660/2010-4
dc.description.sponsorshipIDCAPES: 1915-13-4
dc.identifier.citationBiochimica Et Biophysica Acta-molecular Cell Research. Amsterdam: Elsevier B.V., v. 1843, n. 9, p. 1948-1968, 2014.
dc.publisherElsevier B.V.
dc.relation.ispartofBiochimica Et Biophysica Acta-molecular Cell Research
dc.rightsAcesso aberto
dc.subjectTranslational regulationen
dc.subjectUncharged tRNAen
dc.titleKeeping the eIF2 alpha kinase Gcn2 in checken
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