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J. Biol. Chem., Vol. 280, Issue 46, 38700-38710, November 18, 2005

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Transcriptional Repression of Peroxisome Proliferator-activated Receptor / in Murine Keratinocytes by CCAAT/Enhancer-binding Proteins^*

From the Center for Integrative Genomics, National Center of Competence in Research Frontiers in Genetics, University of Lausanne, CH-1015 Lausanne, Switzerland

The roles of peroxisome proliferator-activated receptors (PPARs) and CCAAT/enhancer-binding proteins (C/EBPs) in keratinocyte and sebocyte differentiation suggest that both families of transcription factors closely interact in the skin. Initial characterization of the mouse PPAR promoter revealed an AP-1 site that is crucial for the regulation of PPAR expression in response to inflammatory cytokines in the skin. We now present evidence for a novel regulatory mechanism of the expression of the PPAR gene by which two members of the C/EBP family of transcription factors inhibit its basal promoter activity in mouse keratinocytes. We first demonstrate that C/EBP and C/EBP, but not C/EBP, inhibit the expression of PPAR through the recruitment of a transcriptional repressor complex containing HDAC-1 to a specific C/EBP binding site on the PPAR promoter. Consistent with this repression, the expression patterns of PPAR and C/EBPs are mutually exclusive in keratinocytes of the interfollicular epidermis and hair follicles in mouse developing skin. This work reveals the importance of the regulatory interplay between PPAR and C/EBP transcription factors in the control of proliferation and differentiation in this organ. Such insights are crucial for the understanding of the molecular control regulating the balance between proliferation and differentiation in many cell types including keratinocytes.

Received for publication, July 18, 2005 , and in revised form, August 18, 2005.

^* This work was supported by Swiss National Science Foundation Grant 3100-065229 (to W. W.) and Grant 3100-108295 (to B. D.) and the Etat de Vaud. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ To whom correspondence may be addressed. Tel.: 41-21-692-4110; Fax: 41-21-692-4115; E-mail: liliane.michalik{at}unil.ch.

² To whom correspondence may be addressed. Tel.: 41-21-692-4110; Fax: 41-21-692-4115; E-mail: walter.wahli{at}unil.ch.

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