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

Abstract

In melanocytes and melanoma cells α-melanocyte stimulating hormone (α-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 1α (HIF1α) 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 α-MSH/cAMP pathway, using MITF as a signal transducer and HIF1α as a target, might contribute to melanoma progression.

c-Kit mutants require hypoxia-inducible factor 1α to transform melanocytes

“…This strict dependency of c-Kit mutants on the microenvironment could explain the low frequency of c-Kit mutations in cutaneous melanoma (around 2%) Beadling et al, 2008). Interestingly, HIF-1a has also been identified as a target for microphthalmia-associated transcription factor (MITF) (Busca et al, 2005). MITF, a transcription factor master regulator of melanocyte differentiation and melanoma proliferation, has been found amplified in around 20% of melanoma (Garraway et al, 2005).…”

BDNF rs6265 methylation and genotype interact on risk for schizophrenia

“…Moreover, BHLHB2 and GADD45B are regulated by hypoxia, since they have a highstringency HIF1 binding site, 53,54 and BHLHB2 represses expression of MITF, 53 a TF stimulating HIF1a expression. 55 Studies in mice have also proved how the basic helix-loop-helix protein BHLHB2 is regulated by neurotrophins and modulate BDNF transcription. 56 As a consequence, we performed an experiment of chromatin immunoprecipitation (ChIP), with the aim of verifying whether these proteins and TFs related to hypoxia could bind the Val allele in the rs6265 region, potentially interacting in a different way in ValVal and ValMet subjects.…”

Malignant melanoma: genetics and therapeutics in the genomic era

“…Pigmentation-associated transcriptional targets of MITF include the pigment enzyme genes tyrosinase, TRP1, TRP2/Dct, which were recognized to contain an evolutionarily conserved consensus promoter/enhancer element that matches the MITF recognition sequence (Bentley et al 1994;Hemesath et al 1994;Yasumoto et al 1994). Additional differentiation-associated genes include Pmel17/silver/gp100 (which encodes the melanoma diagnostic epitope HMB45) (Halaban et al 1996;Baxter and Pavan 2003;Du et al 2003), MelanA/Mart1 , Melastatin (TRPM1) (Miller et al 2004;Zhiqi et al 2004), AIM1 (ocular albinism 4 gene) (Du and Fisher 2002), Ocular albinism 1 gene (OA1) (Vetrini et al 2004), VMD2 (Esumi et al 2004), HIF1␣ (Busca et al 2005), Plasminogen activator inhibitor-1 (Murakami et al 2006), numerous mast cell targets of MITF including Prostaglandin D2, multiple mast cell genes including proteases, various adhesion molecules and others (see Ito et al 2004;Morii et al 2004;Takeda et al 2006 and references therein), and melanocortin 1 receptor (MC1R) in mast cells and possibly in melanocytes (Adachi et al 2000;Smith et al 2001;Aoki and Moro 2002). Numerous additional genes are being identified through expression microarrays, and are liable to reflect the multiple steps involved between signaling, expressing, packaging, and exporting pigment.…”