title: Amino acid availability controls TRB3 transcription in liver through the GCN2/eIF2α/ATF4 pathway.
abstract: In mammals, plasma amino acid concentrations are markedly affected by dietary or pathological conditions. It has been well established that amino acids are involved in the control of gene expression. Up to now, all the information concerning the molecular mechanisms involved in the regulation of gene transcription by amino acid availability has been obtained in cultured cell lines. The present study aims to investigate the mechanisms involved in transcriptional activation of the TRB3 gene following amino acid limitation in mice liver. The results show that TRB3 is up-regulated in the liver of mice fed a leucine-deficient diet and that this induction is quickly reversible. Using transient transfection and chromatin immunoprecipitation approaches in hepatoma cells, we report the characterization of a functional Amino Acid Response Element (AARE) in the TRB3 promoter and the binding of ATF4, ATF2 and C/EBPβ to this AARE sequence. We also provide evidence that only the binding of ATF4 to the AARE plays a crucial role in the amino acid-regulated transcription of TRB3. In mouse liver, we demonstrate that the GCN2/eIF2α/ATF4 pathway is essential for the induction of the TRB3 gene transcription in response to a leucine-deficient diet. Therefore, this work establishes for the first time that the molecular mechanisms involved in the regulation of gene transcription by amino acid availability are functional in mouse liver.
authors.affiliation: INRA, UMR 1019 Nutrition Humaine, Saint Genès Champanelle, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Carraro
authors.forename: Anne-Catherine
authors.initials: AC
authors.lastname: Maurin
authors.forename: Sarah
authors.initials: S
authors.lastname: Lambert-Langlais
authors.forename: Julien
authors.initials: J
authors.lastname: Averous
authors.forename: Cédric
authors.initials: C
authors.lastname: Chaveroux
authors.forename: Laurent
authors.initials: L
authors.lastname: Parry
authors.forename: Céline
authors.initials: C
authors.lastname: Jousse
authors.forename: Daima
authors.initials: D
authors.lastname: Ord
authors.forename: Tõnis
authors.initials: T
authors.lastname: Ord
authors.forename: Pierre
authors.initials: P
authors.lastname: Fafournoux
authors.forename: Alain
authors.initials: A
authors.lastname: Bruhat
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism*; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007930:Leucine / Q000737:chemistry; D008099:Liver / Q000378:metabolism*; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism* / Q000037:antagonists & inhibitors; D012097:Repressor Proteins / Q000378:metabolism*; D020218:Response Elements
chemical_list: C497109:ATF4 protein, human; C081452:Atf4 protein, mouse; D018797:Cell Cycle Proteins; D015852:Eukaryotic Initiation Factor-2; D012097:Repressor Proteins; C474830:TRB3 protein, mouse; C474831:TRIB3 protein, human; D051701:Activating Transcription Factor 4; C529271:EIF2AK4 protein, human; C070634:Eif2ak4 protein, mouse; D017346:Protein Serine-Threonine Kinases; D007930:Leucine