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Free keywords:
Animals
Blotting, Western
Cell Line
Cell Line, Tumor
Cells, Cultured
Chromatin Immunoprecipitation
Colforsin/pharmacology
Cyclic AMP/metabolism
Cyclic AMP-Dependent Protein Kinase Type II
Cyclic AMP-Dependent Protein Kinases/metabolism
DNA Mutational Analysis
Gene Expression Regulation, Enzymologic
Gene Expression Regulation, Neoplastic
Genes, Reporter
Glucocorticoids/metabolism
*Gluconeogenesis
Glucose/*metabolism
Glucose-6-Phosphate/genetics
Hepatocytes/metabolism
Humans
Mutation
Phosphoenolpyruvate Carboxykinase (GTP)/metabolism
Plasmids/metabolism
Promoter Regions, Genetic
Protein Binding
Protein-Arginine N-Methyltransferases/metabolism
RNA Interference
Rats
Signal Transduction
Transcription, Genetic
Transfection
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.
