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J. Biol. Chem., Vol. 281, Issue 41, 30463-30470, October 13, 2006

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p21^WAF1/Cip1 Suppresses Keratinocyte Differentiation Independently of the Cell Cycle through Transcriptional Up-regulation of the IGF-I Gene^*

Vikram Devgan, Bach-Cuc Nguyen, Heysun Oh, and G. Paolo Dotto¹

From the Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129 and Department of Biochemistry, Lausanne University, CH-1066 Epalinges, Switzerland

p21 plays a dual role in keratinocyte growth and differentiation control. It restricts the number of keratinocyte stem cell populations while inhibiting the later stages of differentiation independently of the cell cycle. The molecular/biochemical mechanism for the differentiation suppressive function of p21 is unknown. Here we show that elevated p21 expression leads to activation of MAPK family members in a keratinocyte-specific and cell cycle-independent manner, and up-regulation of MAPK activity can explain the inhibitory effects of p21 on differentiation. p21 induces transcription of several genes with MAPK activation potential. Although several of these genes are induced by p21 in a MAPK-dependent manner, expression of IGF-I is induced upstream of MAPK activation. IGF-I stimulation is by itself sufficient to cause MAPK activation and inhibit differentiation and suppression of IGF-I signaling by knock down of the cognate receptor (IGF-R1), diminishing the ability of p21 to activate MAPK and suppress differentiation. Thus, in keratinocytes, the ability of p21 to suppress differentiation can be explained by cell type-specific activation of the MAPK cascade by transcriptional up-regulation of the IGF-I gene.

Received for publication, May 16, 2006 , and in revised form, July 21, 2006.

^* This work was supported by National Institutes of Health Grants AR39190, CA16038, and CA73796; a grant from the Swiss National Foundation and a grant from the European Union (to G. P. D.); and in part by the Cutaneous Biology Research Center through the Massachusetts General Hospital/Shiseido Co. Ltd. Agreement. 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 Table S1.

¹ To whom correspondence should be addressed: Dept. of Biochemistry, University of Lausanne, Chemin de Bovaresses 155, CH-1066 Epalinges, Switzerland. Tel.: 41-21-692-5720; Fax: 41-21-692-5705; E-mail: Gian-Paolo.Dotto{at}unil.ch.

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