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Submitted on May 4, 2004
Accepted on January 12, 2005
PHYSICALLY INTERACTS WITH C/EBP
TO INHIBIT C/EBP-RESPONSIVE 1-ACID GLYCOPROTEIN GENE EXPRESSION
Laboratoire de Biochimie et de Biologie Cellulaire, EAD 1595, Faculté de Pharmacie, Université Paris XI, France (A.M., A.B., D.P., N.M.-C.); Plate-forme Transcriptome-Protéome, INSERM IFR-75, Faculté de Pharmacie, Université Paris XI, France (C.D.)
* To whom correspondence should be addressed. E-mail: najet.charef{at}cep.u-psud.fr.
Recently, the role of the peroxisome proliferator-activated receptor alpha (PPAR
) in the hepatic inflammatory response has been associated to the decrease of acute phase protein (APP) transcription although the molecular mechanisms are still to be elucidated. Here, we were interested in the regulation by Wy-14643 (PPAR agonist) of 1-acid glycoprotein (AGP), a positive acute phase protein, after stimulation by Dexamethasone (Dex), a major modulator of the inflammatory response. In cultured rat hepatocytes, we demonstrate that PPAR inhibits at the transcriptional level the Dex-induced AGP gene expression. PPAR exerts this inhibitory effect by antagonizing the C/EBP
transcription factor that is involved in Dex-dependent up-regulation of AGP gene expression. Overexpression of C/EBP alleviates the repressive effect of PPAR thus restoring the Dex-stimulated AGP promoter activity. Furthermore, GST pull-down and co-immunoprecipitation experiments evidenced, for the first time, a physical interaction between PPAR and the C-terminal DNA binding region of C/EBP thus preventing it from binding to specific sequence elements of the AGP promoter. Altogether, these results provide an additional molecular mechanism of negative regulation of APP gene expression by sequestration of the C/EBP transcription factor by PPAR and reveal the high potency of the latter in controlling inflammation.
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C/EBP •
1-Acid Glycoprotein •
Dexamethasone
NURSA Molecule Pages Link:
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