title: A mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK)-dependent transcriptional program controls activation of the early growth response 1 (EGR1) gene during amino acid limitation.
abstract: Amino acid (AA) limitation in mammalian cells triggers a collection of signaling cascades jointly referred to as the AA response (AAR). In human HepG2 hepatocellular carcinoma, the early growth response 1 (EGR1) gene was induced by either AA deprivation or endoplasmic reticulum stress. AAR-dependent EGR1 activation was discovered to be independent of the well characterized GCN2-ATF4 pathway and instead dependent on MEK-ERK signaling, one of the MAPK pathways. ChIP showed that constitutively bound ELK1 at the EGR1 proximal promoter region was phosphorylated after AAR activation. Increased p-ELK1 binding was associated with increased de novo recruitment of RNA polymerase II to the EGR1 promoter. EGR1 transcription was not induced in HEK293T cells lacking endogenous MEK activity, but overexpression of exogenous constitutively active MEK in HEK293T cells resulted in increased basal and AAR-induced EGR1 expression. ChIP analysis of the human vascular endothelial growth factor A (VEGF-A) gene, a known EGR1-responsive gene, revealed moderate increases in AAR-induced EGR1 binding within the proximal promoter and highly inducible binding to a site within the first intron. Collectively, these data document a novel AA-activated MEK-ERK-ELK1 signaling mechanism.
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Shands Cancer Center and Center for Nutritional Sciences and.
authors.forename: Jixiu
authors.initials: J
authors.lastname: Shan
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Shands Cancer Center and Center for Nutritional Sciences and.
authors.forename: Mukundh N
authors.initials: MN
authors.lastname: Balasubramanian
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Shands Cancer Center and Center for Nutritional Sciences and.
authors.forename: William
authors.initials: W
authors.lastname: Donelan
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Shands Cancer Center and Center for Nutritional Sciences and.
authors.forename: Lingchen
authors.initials: L
authors.lastname: Fu
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Shands Cancer Center and Center for Nutritional Sciences and.
authors.forename: Jaclyn
authors.initials: J
authors.lastname: Hayner
authors.affiliation: the Department of Molecular Genetics and Microbiology, Genetics Institute, University of Florida College of Medicine, Gainesville, Florida 32610.
authors.forename: Maria-Cecilia
authors.initials: MC
authors.lastname: Lopez
authors.affiliation: the Department of Molecular Genetics and Microbiology, Genetics Institute, University of Florida College of Medicine, Gainesville, Florida 32610.
authors.forename: Henry V
authors.initials: HV
authors.lastname: Baker
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Shands Cancer Center and Center for Nutritional Sciences and mkilberg@ufl.edu.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Kilberg
mesh_terms: D000596:Amino Acids / Q000378:metabolism*; D001483:Base Sequence; D017931:DNA Primers; D051766:Early Growth Response Protein 1 / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D014158:Transcription, Genetic
chemical_list: D000596:Amino Acids; D017931:DNA Primers; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases
keywords: ATF4; Amino Acid; Amino Acid Response; Asparagine Synthetase; Gene Transcription; HepG2 Cells; Hepatocellular Carcinoma; Mitogen-activated Protein Kinase (MAPK); Transcription