Hypoxia-inducible factor 1{alpha} is a new target of microphthalmia-associated transcription factor (MITF) in melanoma cells.
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 1alpha (HIF1alpha) 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 HIF1alpha as a target, might contribute to melanoma progression.
INSERM U597, Biologie et physiopathologie des cellules mélanocytaires, Faculty of Medicine, 06107 Nice cedex 2, France. busca@unice.fr
Roser
R
Buscà
Edurne
E
Berra
Cédric
C
Gaggioli
Mehdi
M
Khaled
Karine
K
Bille
Barbara
B
Marchetti
Raphaël
R
Thyss
Giorgos
G
Fitsialos
Lionel
L
Larribère
Corine
C
Bertolotto
Thierry
T
Virolle
Pascal
P
Barbry
Jacques
J
Pouysségur
Gilles
G
Ponzio
Robert
R
Ballotti
D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D005809:Genes, Regulator / Q000235:genetics; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008544:Melanocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008545:Melanoma / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D051739:Microphthalmia-Associated Transcription Factor; D041681:NIH 3T3 Cells; D011401:Promoter Regions, Genetic / Q000502:physiology; D034622:RNA Interference / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D000521:alpha-MSH / Q000378:metabolism
D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor; C497235:Mitf protein, mouse; D012333:RNA, Messenger; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D000521:alpha-MSH; D000242:Cyclic AMP