title: Coordinated Regulation of the Neutral Amino Acid Transporter SNAT2 and the Protein Phosphatase Subunit GADD34 Promotes Adaptation to Increased Extracellular Osmolarity.
abstract: Cells respond to shrinkage induced by increased extracellular osmolarity via programmed changes in gene transcription and mRNA translation. The immediate response to this stress includes the induction of expression of the neutral amino acid transporter SNAT2. Increased SNAT2-mediated uptake of neutral amino acids is an essential adaptive mechanism for restoring cell volume. In contrast, stress-induced phosphorylation of the α subunit of the translation initiation factor eIF2 (eIF2α) can promote apoptosis. Here we show that the response to mild hyperosmotic stress involves regulation of the phosphorylation of eIF2α by increased levels of GADD34, a regulatory subunit of protein phosphatase 1 (PP1). The induction of GADD34 was dependent on transcriptional control by the c-Jun-binding cAMP response element in the GADD34 gene promoter and posttranscriptional stabilization of its mRNA. This mechanism differs from the regulation of GADD34 expression by other stresses that involve activating transcription factor 4 (ATF4). ATF4 was not translated during hyperosmotic stress despite an increase in eIF2α phosphorylation. The SNAT2-mediated increase in amino acid uptake was enhanced by increased GADD34 levels in a manner involving decreased eIF2α phosphorylation. It is proposed that the induction of the SNAT2/GADD34 axis enhances cell survival by promoting the immediate adaptive response to stress.
authors.affiliation: Departments of Pharmacology, Case Western Reserve University, School of Medicine, Cleveland, Ohio 44106. Electronic address: dawid.krokowski@case.edu.
authors.forename: Dawid
authors.initials: D
authors.lastname: Krokowski
authors.affiliation: Departments of Pharmacology, Case Western Reserve University, School of Medicine, Cleveland, Ohio 44106.
authors.forename: Raul
authors.initials: R
authors.lastname: Jobava
authors.affiliation: Departments of Pharmacology, Case Western Reserve University, School of Medicine, Cleveland, Ohio 44106.
authors.forename: Bo-Jhih
authors.initials: BJ
authors.lastname: Guan
authors.affiliation: Departments of Pharmacology, Case Western Reserve University, School of Medicine, Cleveland, Ohio 44106.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Farabaugh
authors.affiliation: Departments of Pharmacology, Case Western Reserve University, School of Medicine, Cleveland, Ohio 44106.
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
authors.affiliation: Departments of Pharmacology, Case Western Reserve University, School of Medicine, Cleveland, Ohio 44106.
authors.forename: Mithu
authors.initials: M
authors.lastname: Majumder
authors.affiliation: Department of Biomedical, Biotechnological, and Translational Sciences, University of Parma, 43100 Parma, Italy.
authors.forename: Massimiliano G
authors.initials: MG
authors.lastname: Bianchi
authors.affiliation: Departments of Biochemistry, Case Western Reserve University, School of Medicine, Cleveland, Ohio 44106.
authors.forename: Martin D
authors.initials: MD
authors.lastname: Snider
authors.affiliation: Department of Biomedical, Biotechnological, and Translational Sciences, University of Parma, 43100 Parma, Italy.
authors.forename: Ovidio
authors.initials: O
authors.lastname: Bussolati
authors.affiliation: Departments of Pharmacology, Case Western Reserve University, School of Medicine, Cleveland, Ohio 44106. Electronic address: mxh8@case.edu.
authors.forename: Maria
authors.initials: M
authors.lastname: Hatzoglou
mesh_terms: D026924:Amino Acid Transport System A / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002470:Cell Survival; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D009997:Osmotic Pressure; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D054645:Protein Phosphatase 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D026924:Amino Acid Transport System A; D015852:Eukaryotic Initiation Factor-2; C498797:SLC38A2 protein, human; C498798:Slc38a2 protein, mouse; C087519:PPP1R15A protein, human; C513256:Ppp1r15a protein, mouse; D054645:Protein Phosphatase 1
keywords: amino acid transport; apoptosis; eIF2; protein synthesis; stress response