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J. Biol. Chem., Vol. 281, Issue 30, 21321-21331, July 28, 2006

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Slug Regulates Integrin Expression and Cell Proliferation in Human Epidermal Keratinocytes^*

Frances E. Turner¹, Simon Broad², Farhat L. Khanim, Alexa Jeanes, Sonia Talma, Sharon Hughes^¶, Chris Tselepis^¶, and Neil A. Hotchin³

From the School of Biosciences and ^¶School of Medicine, University of Birmingham, Edgbaston B15 2TT, United Kingdom and Cancer Research UK, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom

The human epidermis is a self-renewing epithelial tissue composed of several layers of keratinocytes. Within the epidermis there exists a complex array of cell adhesion structures, and many of the cellular events within the epidermis (differentiation, proliferation, and migration) require that these adhesion structures be remodeled. The link between cell adhesion, proliferation, and differentiation within the epidermis is well established, and in particular, there is strong evidence to link the process of terminal differentiation to integrin adhesion molecule expression and function. In this paper, we have analyzed the role of a transcriptional repressor called Slug in the regulation of adhesion molecule expression and function in epidermal keratinocytes. We report that activation of Slug, which is expressed predominantly in the basal layer of the epidermis, results in down-regulation of a number of cell adhesion molecules, including E-cadherin, and several integrins, including 3, 1, and 4. We demonstrate that Slug binds to the 3 promoter and that repression of 3 transcription by Slug is dependent on an E-box sequence within the promoter. This reduction in integrin expression is reflected in decreased cell adhesion to fibronectin and laminin-5. Despite the reduction in integrin expression and function, we do not observe any increase in differentiation. We do, however, find that activation of Slug results in a significant reduction in keratinocyte proliferation.

Received for publication, September 2, 2005 , and in revised form, May 15, 2006.

^* This work was supported by Medical Research Council Career Establishment Award G9803567 (to N. A. H.). 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.

¹ Supported by a Biotechnology and Biological Sciences Research Council Ph.D. studentship.

² Supported by Cancer Research UK.

³ To whom correspondence should be addressed: School of Biosciences, University of Birmingham, Edgbaston B15 2TT, United Kingdom. Tel.: 44-121-414-5412; Fax: 44-121-414-5925; E-mail: n.a.hotchin{at}bham.ac.uk.

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