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J. Biol. Chem., Vol. 282, Issue 19, 14140-14147, May 11, 2007

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Up-regulation of MET Expression by -Melanocyte-stimulating Hormone and MITF Allows Hepatocyte Growth Factor to Protect Melanocytes and Melanoma Cells from Apoptosis^*

Laurent Beuret¹, Enrica Flori^¶, Christophe Denoyelle, Karine Bille, Roser Busca, Mauro Picardo^¶, Corine Bertolotto, and Robert Ballotti²

From the INSERM, U597, Biologie et Pathologies des Cellules Mélanocytaires: de la Pigmentation Cutanée au Mélanome, Equipe labellisée par la Ligue Nationale contre le Cancer, 06107 Nice Cedex 2, France, the Université de Nice Sophia-Antipolis, UFR Médecine, Nice, France, and the ^¶Laboratorio di Fisiopatologia Cutanea, Istituto Dermatologico San Gallicano, Instituti di Ricovero e Cura a Carattere Scientifico, 00144 Rome, Italy

The MET proto-oncogene encodes for the hepatocyte growth factor (HGF) receptor, a plasma membrane tyrosine kinase that is involved in melanocyte growth and melanoma development. In mouse melanoma cells, Met expression is increased by MSH via the activation of the cAMP pathway. However, the mechanism by which cAMP regulates MET and the biological consequences of this increase were not known. In the present report, we show that MSH regulates MET expression in both human melanocytes and mouse melanoma cells through a transcriptional mechanism that requires MITF. Furthermore, the adenovirus driven expression of MITF is sufficient to increase MET in melanoma cells. Functional analysis of the MET promoter allows us to identify an E-box motif conserved in both human and mouse promoter that mediates the effect of MITF. Interestingly, up-regulation of MET expression by cAMP leads to an exacerbated HGF signaling and allows HGF to protect melanocytes and melanoma cells from apoptosis. Thus, physiological stimuli or pathological events that would induce MITF expression may lead to increased MET expression thereby favoring melanoma survival. These observations strengthen the roles of MITF and MET in melanoma development.

Received for publication, December 18, 2006 , and in revised form, March 12, 2007.

^* 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 fellowship from "La Ligue Nationale Contre le Cancer."

² To whom correspondence should be addressed. Tel.: 33-4-93-37-77-90; Fax: 33-4-93-81-14-04; E-mail: ballotti{at}unice.fr.

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