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J. Biol. Chem., Vol. 282, Issue 20, 15090-15102, May 18, 2007

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Transcriptional Signature of Epidermal Keratinocytes Subjected to in Vitro Scratch Wounding Reveals Selective Roles for ERK1/2, p38, and Phosphatidylinositol 3-Kinase Signaling Pathways^*

Giorgos Fitsialos, Anne-Amandine Chassot¹, Laurent Turchi², Manal A. Dayem^¶||, Kevin LeBrigand^¶, Chimène Moreilhon^¶||, Guerrino Meneguzzi, Roser Buscà, Bernard Mari^¶||, Pascal Barbry^¶||, and Gilles Ponzio³

From the INSERM, U634, 28 Avenue de Valombrose, F-06107 Nice cedex 2, France, IFR50, Faculté de Médecine, Université de Nice Sophia Antipolis, 28 Avenue de Valombrose, F-06107 Nice cedex 2, France, ^¶CNRS, Institut de Pharmacologie Moléculaire et Cellulaire, UMR6097, 660 Route des Lucioles, F-06560 Sophia Antipolis, France, and the ^||Université de Nice Sophia Antipolis, Institut de Pharmacologie Moléculaire et Cellulaire, UMR6097, 660 Route des Lucioles, F-06560 Sophia Antipolis, France

Covering denuded dermal surfaces after injury requires migration, proliferation, and differentiation of skin keratinocytes. To clarify the major traits controlling these intermingled biological events, we surveyed the genomic modifications occurring during the course of a scratch wound closure of cultured human keratinocytes. Using a DNA microarray approach, we report the identification of 161 new markers of epidermal repair. Expression data, combined with functional analysis performed with specific inhibitors of ERK, p38^MAPK and phosphatidylinositol 3-kinase (PI3K), demonstrate that kinase pathways exert very selective functions by precisely controlling the expression of specific genes. Inhibition of the ERK pathway totally blocks the wound closure and inactivates many early transcription factors and EGF-type growth factors. p38^MAPK inhibition only delays "healing," probably in line with the control of genes involved in the propagation of injury-initiated signaling. In contrast, PI3K inhibition accelerates the scratch closure and potentiates the scratch-dependent stimulation of three genes related to epithelial cell transformation, namely HAS3, HBEGF, and ETS1. Our results define in vitro human keratinocyte wound closure as a repair process resulting from a fine balance between positive signals controlled by ERK and p38^MAPK and negative ones triggered by PI3K. The perturbation of any of these pathways might lead to dysfunction in the healing process, similar to those observed in pathological wounding phenotypes, such as hypertrophic scars or keloids.

Received for publication, June 26, 2006 , and in revised form, March 12, 2007.

^* This work was supported by grants from INSERM, l'Association pour la Recherche contre le Cancer (Grants 5965 and 4500), Ministère de l'Education Nationale et de la Recherche Grants ACI TS/0220045, the Réseau National Genopoles, the Association "Vaincre la Mucoviscidose," and Institut National du Cancer (INCA) Grant PL079. 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 data.

¹ Recipient of a fellowship from the INSERM/Région PACA and from la Ligue Nationale contre le Cancer.

² Recipient of a fellowship of the Centre Hospitalier Universitaire de Nice.

³ To whom correspondence should be addressed: INSERM U634, 28 Ave. de Valombrose, F-06107 Nice cedex 2, France. Tel.: 33-493377753; Fax: 33-493811404; E-mail: ponzio{at}unice.fr.

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