title: c-Myc is required for the CHREBP-dependent activation of glucose-responsive genes.
abstract: Glucose regulates programs of gene expression that orchestrate changes in cellular phenotype in several metabolically active tissues. Carbohydrate response element-binding protein (ChREBP) and its binding partner, Mlx, mediate glucose-regulated gene expression by binding to carbohydrate response elements on target genes, such as the prototypical glucose-responsive gene, liver-type pyruvate kinase (Pklr). c-Myc is also required for the glucose response of the Pklr gene, although the relationship between c-Myc and ChREBP has not been defined. Here we describe the molecular events of the glucose-mediated activation of Pklr and determine the effects of decreasing the activity or abundance of c-Myc on this process. Time-course chromatin immunoprecipitation revealed a set of transcription factors [hepatocyte nuclear factor (HNF)1alpha, HNF4alpha, and RNA polymerase II (Pol II)] constitutively resident on the Pklr promoter, with a relative enrichment of acetylated histones 3 and 4 in the same region of the gene. Glucose did not affect HNF1alpha binding or the acetylation of histones H3 or H4. By contrast, glucose promoted the recruitment of ChREBP and c-Myc and increased the occupancy of HNF4alpha and RNA Pol II, which were coincident with the glucose-mediated increase in transcription as determined by a nuclear run-on assay. Depletion of c-Myc activity using a small molecule inhibitor (10058-F4/1RH) abolished the glucose-mediated recruitment of HNF4alpha, ChREBP, and RNA Pol II, without affecting basal gene expression, histone acetylation, and HNF1alpha or basal HNF4alpha occupancy. The activation and recruitment of ChREBP to several glucose-responsive genes were blocked by 1RH, indicating a general necessity for c-Myc in this process.
authors.affiliation: Department of Medicine, Division of Endocrinology and Metabolism, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Pili
authors.initials: P
authors.lastname: Zhang
authors.forename: Mallikarjurna R
authors.initials: MR
authors.lastname: Metukuri
authors.forename: Sharell M
authors.initials: SM
authors.lastname: Bindom
authors.forename: Edward V
authors.initials: EV
authors.lastname: Prochownik
authors.forename: Robert M
authors.initials: RM
authors.lastname: O'Doherty
authors.forename: Donald K
authors.initials: DK
authors.lastname: Scott
mesh_terms: D000818:Animals; D001483:Base Sequence; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism*; D001665:Binding Sites; D045744:Cell Line, Tumor; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009928:Organ Specificity / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D011770:Pyruvate Kinase / Q000235:genetics; D051381:Rats; D013844:Thiazoles / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects*
chemical_list: C524814:5-(4-ethylbenzylidene)-2-thioxothiazolidin-4-one; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C499329:Max protein, rat; C442825:Mlxipl protein, rat; D016271:Proto-Oncogene Proteins c-myc; D013844:Thiazoles; D014157:Transcription Factors; D011770:Pyruvate Kinase; D005947:Glucose
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