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Published online 27 June 2005. doi:10.1083/jcb.200501067
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 170, Number 1, 49-59
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Article

 Hypoxia-inducible factor 1{alpha} is a new target of microphthalmia-associated transcription factor (MITF) in melanoma cells

Roser Buscà1, Edurne Berra3, Cédric Gaggioli1, Mehdi Khaled1, Karine Bille1, Barbara Marchetti1, Raphaël Thyss2, Giorgos Fitsialos2, Lionel Larribère1, Corine Bertolotto1, Thierry Virolle2, Pascal Barbry4, Jacques Pouysségur3, Gilles Ponzio2, and Robert Ballotti1

1 INSERM U597, Biologie et physiopathologie des cellules mélanocytaires, Faculty of Medicine, 06107 Nice cedex 2, France
2 INSERM U634, Faculty of Medicine, 06107 Nice cedex 2, France
3 CNRS UMR 6543, Centre Antoine Lacassagne, 06189 Nice cedex 2, France
4 CNRS/UNSA UMR 6097, IPMC, 06560 Sophia Antipolis, France

Correspondence to Roser Buscà: busca{at}unice.fr

In melanocytes and melanoma cells {alpha}-melanocyte stimulating hormone ({alpha}-MSH), via the cAMP pathway, elicits a large array of biological responses that control melanocyte differentiation and influence melanoma development or susceptibility. In this work, we show that cAMP transcriptionally activates Hif1a gene in a melanocyte cell–specific manner and increases the expression of a functional hypoxia-inducible factor 1{alpha} (HIF1{alpha}) protein resulting in a stimulation of Vegf expression. Interestingly, we report that the melanocyte-specific transcription factor, microphthalmia-associated transcription factor (MITF), binds to the Hif1a promoter and strongly stimulates its transcriptional activity. Further, MITF "silencing" abrogates the cAMP effect on Hif1a expression, and overexpression of MITF in human melanoma cells is sufficient to stimulate HIF1A mRNA. Our data demonstrate that Hif1a is a new MITF target gene and that MITF mediates the cAMP stimulation of Hif1a in melanocytes and melanoma cells. Importantly, we provide results demonstrating that HIF1 plays a pro-survival role in this cell system. We therefore conclude that the {alpha}-MSH/cAMP pathway, using MITF as a signal transducer and HIF1{alpha} as a target, might contribute to melanoma progression.

Abbreviations used in this paper: {alpha}-MSH, {alpha}-melanocyte stimulating hormone; ERK2, extracellular signal-regulated kinase 2; HIF1{alpha}, hypoxia-inducible factor 1{alpha}; HRE, hypoxia-responsive element; MC1R, melanocortin-1 receptor; MITF, microphthalmia-associated transcription factor; NHM, normal human melanocytes; PHD2, prolyl-hydroxylase 2; siRNA, small interference RNA; VEGF, vascular endothelial growth factor.


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