The pancreatic duodenal homeobox-1 protein (Pdx-1) interacts with histone deacetylases Hdac-1 and Hdac-2 on low levels of glucose.
We have previously demonstrated that high concentrations of glucose stimulate insulin gene expression by causing hyperacetylation of histone H4 at the insulin gene promoter. Furthermore, we have shown that the glucose-mediated hyperacetylation of histone H4 depends on the recruitment of the histone acetyltransferase p300 by the beta cell-specific transcription factor Pdx-1. In this study, we demonstrate that the histone deacetylases Hdac-1 and Hdac-2 are rapidly recruited to the insulin promoter in the mouse insulinoma cell line MIN6 when cells are switched from high to low glucose media. Moreover, we demonstrate that the beta cell-specific homeodomain protein Pdx-1 interacts with histone deacetylases Hdac-1 and Hdac-2 at low levels of glucose. In vitro studies indicate that the interaction between Pdx-1 and Hdac-1 or Hdac-2 is direct and requires the C terminus of Pdx-1. Treatment of MIN6 cells with okadaic acid, which inhibits the activity of protein phosphatases, abolishes the interaction of Pdx-1 with Hdac-1 and Hdac-2 on low levels of glucose, suggesting the requirement of a dephosphorylation event for this interaction to occur. These data indicate that insulin gene expression is decreased on low levels of glucose by recruitment of Hdac-1 and Hdac-2 to the insulin promoter by the transcription factor Pdx-1.
Mosley
Amber L
AL
Department of Molecular and Cellular Biochemistry, Chandler Medical Center, University of Kentucky, Lexington, Kentucky 40536, USA.
Ozcan
Sabire
S
D000107:Acetylation; D000818:Animals; D003470:Culture Media; D004247:DNA / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000008:administration & dosage*; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D018398:Homeodomain Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D007163:Immunosorbent Techniques; D007328:Insulin / Q000235:genetics; D007340:Insulinoma; D051379:Mice; D019319:Okadaic Acid / Q000494:pharmacology; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship; D015534:Trans-Activators / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured
D003470:Culture Media; D006657:Histones; D018398:Homeodomain Proteins; D007328:Insulin; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D019319:Okadaic Acid; D004247:DNA; C484389:Hdac1 protein, mouse; C533424:Hdac2 protein, mouse; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases; D005947:Glucose