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J. Biol. Chem., Vol. 283, Issue 18, 12635-12642, May 2, 2008

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Microphthalmia-associated Transcription Factor Regulates RAB27A Gene Expression and Controls Melanosome Transport^*

Christine Chiaverini^¶1, Laurent Beuret², Enrica Flori^||, Roser Busca³, Patricia Abbe, Karine Bille, Philippe Bahadoran^¶, Jean-Paul Ortonne^¶, Corine Bertolotto^¶, and Robert Ballotti^¶4

From the INSERM U895, Biologie et Pathologies des Cellules Mélanocytaires de la Pigmentation Cutanée au Mélanome 28, avenue de Valombrose, 06107 Nice Cedex 2, France, the Université de Nice Sophia-Antipolis, UFR Médecine, Nice, F-06107, France, the ^¶CHU Nice, Department of Dermatology, 152, route de Saint Antoine de Ginestière, 06200 Nice, France, and ^||Laboratorio di Fisiopatologia Cutanea, Istituto Dermatologico San Gallicano, IRCCS, 00153-Roma, Italy

Melanosomes are lysosome-related organelles specialized in melanin synthesis and transport. In this study, we show that microphthalmia-associated transcription factor (MITF) silencing induces melanosome gathering around the nucleus and causes the relocalization of Rab27A, Slac2a-Mlph, and Myo5a that control the transport of melanosomes on the actin network. In an attempt to elucidate the mechanism by which MITF controls melanosome distribution, we identify RAB27A as a new MITF target gene. Indeed, MITF silencing leads to a dramatic decrease in Rab27A expression and blocks the stimulation of Rab27A expression evoked by cAMP. Further, forced expression of MITF increases Rab27A expression, indicating that MITF is required and sufficient for Rab27A expression in melanoma cells. MITF binds to two E-boxes in the proximal region of the Rab27A promoter and stimulates its transcriptional activity. Finally, re-expression of Rab27A, in MITF-depleted cells, restores the transport of melanosomes to the cell periphery. These results show that RAB27A is a new direct transcriptional target of MITF and link MITF to melanosome transport, another key parameter of melanocyte differentiation and skin pigmentation. Interestingly, Rab27A is involved in other fundamental physiological functions, such as the transport of lytic granules and insulin secretion. Thus our results, deciphering the mechanism of Rab27A transcriptional regulation, have an interest that goes beyond the skin pigmentation field.

Received for publication, January 7, 2007 , and in revised form, February 13, 2008.

^* 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 Recipient of a fellowship from the Fondation pour la Recherche Médicale.

² Supported by La Ligue contre le Cancer.

³ Present address: INSERM Unité 634, 28, avenue de Valombrose, 06107 Nice Cedex 2, France.

⁴ To whom correspondence should be addressed: INSERM U895, Biologie et Pathologies des Cellules Mélanocytaires: de la Pigmentation Cutanée au Mélanome, 28, avenue de Valombrose, 06107 Nice Cedex 2, France. Tel.: 33-4-93-37-76-99; Fax: 4-93-81-14-04; E-mail: ballotti{at}unice.fr.

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