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

Wang XL, Herzog B, Waltner-Law M, Hall RK, Shiota M, Granner DK
J Biol Chem. 2004 279 (33): 34191-200

PMID: 15166231 · DOI:10.1074/jbc.M403455200

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.

MeSH Terms (32)

Animals Antineoplastic Agents, Hormonal Blotting, Western Carcinoma, Hepatocellular Cell Line Cell Line, Tumor Chromatin Dexamethasone Drug Synergism E1A-Associated p300 Protein Gene Expression Regulation, Enzymologic Genes, Reporter Glucocorticoids Hepatocytes Humans Ligands Liver Liver Neoplasms Luciferases Mutation Nuclear Proteins Phosphoenolpyruvate Carboxykinase (ATP) Plasmids Precipitin Tests Promoter Regions, Genetic Protein Structure, Tertiary Rats Reverse Transcriptase Polymerase Chain Reaction RNA Polymerase II Trans-Activators Transfection Tretinoin

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