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

Buscà R, Berra E, Gaggioli C, Khaled M, Bille K, Marchetti B, Thyss R, Fitsialos G, Larribère L, Bertolotto C, Virolle T, Barbry P, Pouysségur J, Ponzio G, Ballotti R - J. Cell Biol. (2005)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: INSERM U597, Biologie et physiopathologie des cellules mélanocytaires, Faculty of Medicine, 06107 Nice cedex 2, France. busca@unice.fr

ABSTRACT
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.

Show MeSH

Related in: MedlinePlus

Model for the mechanisms of cAMP induction of HIF1α expression. α-MSH, by up-regulating the cAMP pathway, increases MITF expression. MITF binds and transactivates the Hif1a promoter, thereby increasing the expression of Hif1a gene and protein in a melanocyte cell–specific manner. HIF1α dimerizes with HIF1β to constitute a functional HIF1 transcription factor that is capable of activating target genes such as Vegf and up-regulate other genes involved in melanocyte cell survival and angiogenesis to participate in melanoma development and behavior.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2171372&req=5

fig7: Model for the mechanisms of cAMP induction of HIF1α expression. α-MSH, by up-regulating the cAMP pathway, increases MITF expression. MITF binds and transactivates the Hif1a promoter, thereby increasing the expression of Hif1a gene and protein in a melanocyte cell–specific manner. HIF1α dimerizes with HIF1β to constitute a functional HIF1 transcription factor that is capable of activating target genes such as Vegf and up-regulate other genes involved in melanocyte cell survival and angiogenesis to participate in melanoma development and behavior.

Mentions: We demonstrate for the first time that cAMP regulates Hif1a at a transcriptional level, leading to increased expression of HIF1α mRNA and protein. HIF1α forms a HIF1 complex that is functional and able to transactivate target genes such as Vegf. Very interestingly, HIF1α induction by cAMP is restricted to melanocyte cells, prompting us to propose a cell-specific regulation through the melanocyte-specific transcription factor MITF. We demonstrate that MITF binds and transactivates the Hif1a promoter, and the overexpression of MITF is sufficient to increase Hif1a mRNA levels. Furthermore, by silencing MITF or Hif1α expression, we show that cAMP-induced HIF1α expression is mediated by MITF, and that the MITF/HIF1α pathway mediates the cAMP induction of Vegf expression (a model illustrating these conclusions is shown in Fig. 7). We therefore define Hif1a as a new MITF target gene and we provide data revealing the pro-survival role of the MITF-HIF1 cascade in melanoma cells.


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

Buscà R, Berra E, Gaggioli C, Khaled M, Bille K, Marchetti B, Thyss R, Fitsialos G, Larribère L, Bertolotto C, Virolle T, Barbry P, Pouysségur J, Ponzio G, Ballotti R - J. Cell Biol. (2005)

Model for the mechanisms of cAMP induction of HIF1α expression. α-MSH, by up-regulating the cAMP pathway, increases MITF expression. MITF binds and transactivates the Hif1a promoter, thereby increasing the expression of Hif1a gene and protein in a melanocyte cell–specific manner. HIF1α dimerizes with HIF1β to constitute a functional HIF1 transcription factor that is capable of activating target genes such as Vegf and up-regulate other genes involved in melanocyte cell survival and angiogenesis to participate in melanoma development and behavior.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2171372&req=5

fig7: Model for the mechanisms of cAMP induction of HIF1α expression. α-MSH, by up-regulating the cAMP pathway, increases MITF expression. MITF binds and transactivates the Hif1a promoter, thereby increasing the expression of Hif1a gene and protein in a melanocyte cell–specific manner. HIF1α dimerizes with HIF1β to constitute a functional HIF1 transcription factor that is capable of activating target genes such as Vegf and up-regulate other genes involved in melanocyte cell survival and angiogenesis to participate in melanoma development and behavior.
Mentions: We demonstrate for the first time that cAMP regulates Hif1a at a transcriptional level, leading to increased expression of HIF1α mRNA and protein. HIF1α forms a HIF1 complex that is functional and able to transactivate target genes such as Vegf. Very interestingly, HIF1α induction by cAMP is restricted to melanocyte cells, prompting us to propose a cell-specific regulation through the melanocyte-specific transcription factor MITF. We demonstrate that MITF binds and transactivates the Hif1a promoter, and the overexpression of MITF is sufficient to increase Hif1a mRNA levels. Furthermore, by silencing MITF or Hif1α expression, we show that cAMP-induced HIF1α expression is mediated by MITF, and that the MITF/HIF1α pathway mediates the cAMP induction of Vegf expression (a model illustrating these conclusions is shown in Fig. 7). We therefore define Hif1a as a new MITF target gene and we provide data revealing the pro-survival role of the MITF-HIF1 cascade in melanoma cells.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: INSERM U597, Biologie et physiopathologie des cellules mélanocytaires, Faculty of Medicine, 06107 Nice cedex 2, France. busca@unice.fr

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus