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The synergistic effect of dexamethasone and all-trans-retinoic acid on hepatic phosphoenolpyruvate carboxykinase gene expression involves the coactivator p300
Journal article   Open access   Peer reviewed

The synergistic effect of dexamethasone and all-trans-retinoic acid on hepatic phosphoenolpyruvate carboxykinase gene expression involves the coactivator p300

Xiaohui L Wang, Birger Herzog, Mary Waltner-Law, Robert K Hall, Masakazu Shiota and Daryl K Granner
The Journal of biological chemistry, Vol.279(33), pp.34191-34200
08/13/2004
DOI: 10.1074/jbc.M403455200
PMID: 15166231
url
https://doi.org/10.1074/jbc.M403455200View
Published (Version of record) Open Access

Abstract

Activation of phosphoenolpyruvate carboxykinase (PEPCK) gene transcription in response to all-trans-retinoic acid (RA) or a glucocorticoid such as dexamethasone (Dex) requires a distinct arrangement of DNA-response elements and their cognate transcription activators on the gene promoter. Two of the accessory factor-binding elements involved in the Dex response (gAF1 and gAF3) coincide with the DNA-response elements involved in the RA response. We demonstrate here that the combination of Dex/RA has a synergistic effect on endogenous PEPCK gene expression in rat hepatocytes and H4IIE hepatoma cells. Reporter gene studies show that the gAF3 element and one of the two glucocorticoid receptor-binding elements (GR1) are most important for this effect. Chromatin immunoprecipitation assays revealed that when H4IIE cells were treated with Dex/RA, ligand-activated retinoic acid receptors (retinoic acid receptor/retinoid X receptor) and glucocorticoid receptors are recruited to this gene promoter, as are the transcription coregulators p300, CREB-binding protein, p/CIP, and SRC-1. Notably, the recruitment of p300 and RNA polymerase II to the PEPCK promoter is increased by the combined Dex/RA treatment compared with Dex or RA treatment alone. The functional importance of p300 in the Dex/RA response is illustrated by the observation that selective reduction of this coactivator, but not that of CREB-binding protein, abolishes the synergistic effect in H4IIE cells.
 Chromatin - metabolism Glucocorticoids - administration & dosage Liver - enzymology Luciferases - metabolism Humans E1A-Associated p300 Protein Hepatocytes - metabolism RNA Polymerase II - metabolism Phosphoenolpyruvate Carboxykinase (ATP) - biosynthesis Transfection Tretinoin - metabolism Glucocorticoids - metabolism Genes, Reporter Protein Structure, Tertiary Cell Line Promoter Regions, Genetic Tretinoin - administration & dosage Dexamethasone - administration & dosage Antineoplastic Agents, Hormonal - administration & dosage Rats Nuclear Proteins - metabolism Reverse Transcriptase Polymerase Chain Reaction Plasmids - metabolism Blotting, Western Precipitin Tests Drug Synergism Gene Expression Regulation, Enzymologic Animals Liver Neoplasms - metabolism Cell Line, Tumor Ligands Trans-Activators - metabolism Mutation Carcinoma, Hepatocellular - metabolism

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