AMP-activated protein kinase regulates PEPCK gene expression by direct phosphorylation of a novel zinc finger transcription factor.
AMP-activated protein kinase (AMPK) acts as an intracellular sensor for maintaining the energy balance. Activation of AMPK switches on ATP-generating process while switches off ATP-consuming process. It achieves these effects by phosphorylation of downstream metabolic enzymes. It has been proposed that AMPK also regulates gene expression through phosphorylation of certain transcription factors; however its molecular mechanism is not fully understood. Here we show the cloning and characterization of a novel zinc finger transcription factor referred to as AREBP. AREBP is phosphorylated at Ser(470) by AMPK. Phosphorylation reduces the DNA-binding activity of AREBP. Transient transfection experiments indicate that wild-type AREBP, but not Ser(470) to Ala(470) substituted non-phosphorylating mutant, represses gene expression of the phosphoenolpyruvate carboxykinase (PEPCK), a key enzyme of gluconeogenesis. RNA interference-mediated reduction of endogenous AREBP expression attenuates AMPK-induced PEPCK down-regulation. These results implicate AREBP as a novel key modulator of PEPCK gene expression regulated by AMPK.
Inoue
Erina
E
Nutritional Epidemiology Program, Bio-Index Project, National Institute of Health and Nutrition, 1-23-1 Toyama, Shinjyuku, Tokyo 162-8636, Japan.
Yamauchi
Jun
J
D055372:AMP-Activated Protein Kinases; D000595:Amino Acid Sequence; D000818:Animals; D003001:Cloning, Molecular; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D015971:Gene Expression Regulation, Enzymologic; D005943:Gluconeogenesis / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000502:physiology*; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000235:genetics*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D051381:Rats; D020218:Response Elements / Q000235:genetics; D012694:Serine / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016335:Zinc Fingers
D004268:DNA-Binding Proteins; D009097:Multienzyme Complexes; D014157:Transcription Factors; C516332:ZNF692 protein, human; D012694:Serine; D004247:DNA; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D019764:Phosphoenolpyruvate Carboxykinase (ATP)