title: Signal-dependent control of gluconeogenic key enzyme genes through coactivator-associated arginine methyltransferase 1.
abstract: Together with impaired glucose uptake in skeletal muscle, elevated hepatic gluconeogenesis is largely responsible for the hyperglycemic phenotype in type II diabetic patients. Intracellular glucocorticoid and cyclic adenosine monophosphate (cAMP)/protein kinase A-dependent signaling pathways contribute to aberrant hepatic glucose production through the induction of gluconeogenic enzyme gene expression. Here we show that the coactivator-associated arginine methyltransferase 1 (CARM1) is required for cAMP-mediated activation of rate-limiting gluconeogenic phosphoenolpyruvate carboxykinase (PEPCK; EC 4.1.1.32) and glucose-6-phosphatase genes. Mutational analysis showed that CARM1 mediates its effect via the cAMP-responsive element within the PEPCK promoter, which is identified here as a CARM1 target in vivo. In hepatocytes, endogenous CARM1 physically interacts with cAMP-responsive element binding factor CREB and is recruited to the PEPCK and glucose-6-phosphatase promoters in a cAMP-dependent manner associated with increased promoter methylation. CARM1 might, therefore, represent a critical component of cAMP-dependent glucose metabolism in the liver.
authors.affiliation: Department of Molecular Metabolic Control, German Cancer Research Center Heidelberg, Heidelberg 69120, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Krones-Herzig
authors.forename: Andrea
authors.initials: A
authors.lastname: Mesaros
authors.forename: Dagmar
authors.initials: D
authors.lastname: Metzger
authors.forename: Anja
authors.initials: A
authors.lastname: Ziegler
authors.forename: Ulrike
authors.initials: U
authors.lastname: Lemke
authors.forename: Jens C
authors.initials: JC
authors.lastname: Brüning
authors.forename: Stephan
authors.initials: S
authors.lastname: Herzig
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004252:DNA Mutational Analysis; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D005938:Glucocorticoids / Q000378:metabolism; D005943:Gluconeogenesis; D005947:Glucose / Q000378:metabolism*; D019298:Glucose-6-Phosphate / Q000235:genetics; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D009154:Mutation; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011484:Protein-Arginine N-Methyltransferases / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D015398:Signal Transduction; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: D005938:Glucocorticoids; D005576:Colforsin; D019298:Glucose-6-Phosphate; D000242:Cyclic AMP; D011484:Protein-Arginine N-Methyltransferases; C119966:coactivator-associated arginine methyltransferase 1; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D005947:Glucose