Involvement of Microphthalmia in the Inhibition of Melanocyte Lineage Differentiation and of Melanogenesis by Agouti Signal Protein

Aberdam, Édith; Bertolotto, Corine; Sviderskaya, Elena V.; Thillot, V de; Hemesath, Timothy J.; Fisher, David E.; Bennett, Dorothy C.; Ortonne, Jean‐Paul; Ballotti, Robert

doi:10.1074/jbc.273.31.19560

Cited by 174 publications

(76 citation statements)

References 44 publications

(40 reference statements)

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“…Mitf, Tyr, Tyrp1, Dct, and Si were down-regulated, whereas Tcf4 was upregulated. Previous studies reporting a similar effect of ASP on those genes (15,16,39,40) were consistent with our data. We identified 16 other pigment-related genes whose transcription was repressed by ASP and 2 transcription factors which were upregulated (Lef1 and Tcfap2a/Ap2a).…”

Section: Resultssupporting

confidence: 82%

Microarray analysis sheds light on the dedifferentiating role of agouti signal protein in murine melanocytes via the Mc1r

Pape

Passeron

Giubellino

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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The melanocortin-1 receptor (MC1R) is a key regulator of pigmentation in mammals and is tightly linked to an increased risk of skin cancers, including melanoma, in humans. Physiologically activated by ␣-melanocyte stimulating hormone (␣MSH), MC1R function can be antagonized by a secreted factor, agouti signal protein (ASP), which is responsible for the lighter phenotypes in mammals (including humans), and is also associated with increased risk of skin cancer. It is therefore of great interest to characterize the molecular effects elicited by those MC1R ligands. In this study, we determined the gene expression profiles of murine melan-a melanocytes treated with ASP or ␣MSH over a 4-day time course using genome-wide oligonucleotide microarrays. As expected, there were significant reductions in expression of numerous melanogenic proteins elicited by ASP, which correlates with its inhibition of pigmentation. ASP also unexpectedly modulated the expression of genes involved in various other cellular pathways, including glutathione synthesis and redox metabolism. Many genes up-regulated by ASP are involved in morphogenesis (especially in nervous system development), cell adhesion, and extracellular matrix-receptor interactions. Concomitantly, ASP enhanced the migratory potential and the invasiveness of melanocytic cells in vitro. These results demonstrate the role of ASP in the dedifferentiation of melanocytes, identify pigment-related genes targeted by ASP and by ␣MSH, and provide insights into the pleiotropic molecular effects of MC1R signaling that may function during development and may affect skin cancer risk.pigmentation ͉ skin cancer A major determinant of the pigment phenotype of the skin is the melanocortin-1 receptor (MC1R), a G protein coupled receptor (GPCR) that regulates many functional aspects of melanocytes, including their dendricity, melanogenesis, and proliferation (1, 2). MC1R function can be activated by ␣-melanocyte-stimulating hormone (␣MSH), a POMC-derived peptide whose production in the skin (3) is increased by exposure to UV radiation (UV) via a p53-dependent mechanism (4). This interaction triggers increased melanin production (5, 6) and stimulates the repair of DNA photoproducts caused by UV (7-9), a phenomenon also induced by forskolin (10). It is therefore not surprising that MC1R polymorphisms are associated with a lighter pigment phenotype, including red hair/fair skin (11), with poor tanning responses (12) and an increased risk for melanoma and other skin cancers (13,14).MC1R signaling can be inhibited by the product of the agouti locus, agouti signal protein (ASP in mice, ASIP in humans), which acts as an inverse agonist of the murine Mc1r (15,16). In mice, ASP is expressed in skin and testis and during embryogenesis. The spatiotemporal expression of ASP in skin is responsible for the agouti hair phenotype (a pheomelanic band against a dark eumelanic background) and for the pale coloration on the neck, breast, and ventral surface (17). A high degree of polymorphism in the promoter of t...

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Section: Resultssupporting

confidence: 82%

Microarray analysis sheds light on the dedifferentiating role of agouti signal protein in murine melanocytes via the Mc1r

Pape

Passeron

Giubellino

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…It has been shown that a-MSH also promotes the differentiation of murine melanoblasts into mature melanocytes, and that this induction is also inhibited by ASP. In melanoblasts, the expression of microphthalmia and its binding to the M box regulatory element present in the promoters of melanogenic enzymes, is also inhibited by ASP (72). Taken together, these studies indicate a key regulatory role for ASP in melanocyte differentiation and melanogenesis, and again point to the involvement of microphthalmia in these processes.…”

Section: The Camp Pathway and Agouti Signalingmentioning

confidence: 63%

Cyclic AMP a Key Messenger in the Regulation of Skin Pigmentation

Buscà

Ballotti

2000

Pigment Cell Research

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719

640

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In humans, stimulation of skin pigmentation over the basal constitutive level, which we commonly call tanning, is physiologically stimulated by ultraviolet (UV) radiation of the solar light. UV-induced skin darkening involves an increase in the melanocyte number as well as a stimulation of melanin neosynthesis and melanocyte dendricity, a crucial morphological feature required for melanin transfer to keratinocytes. These events, corresponding to the final steps of melanocyte differentiation, play a central role in the tanning response and are subjected to an accurate research which aims to understand the precise mechanisms governing their regulation. In the present review, we will mainly focus our attention on the molecular processes involved in the regulation of melanogenesis.

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“…However, little is known about the mechanism of action of ASP on melanocytes. It has been demonstrated that MITF is inhibited by ASP (39). The basic helix-loop-helix transcription factor (ITF2) has been shown to be involved in the action of ASP on pigmentation (40).…”

Section: Figmentioning

confidence: 99%

SOX9 is a key player in ultraviolet B-induced melanocyte differentiation and pigmentation

Passeron

Valencia

Bertolotto

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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117

115

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SOX (SRY type HMG box) proteins are transcription factors that are predominantly known for their roles during development. During melanocyte development from the neural crest, SOX10 regulates microphthalmia-associated transcription factor, which controls a set of genes critical for pigment cell development and pigmentation, including dopachrome tautomerase and tyrosinase. We report here that another SOX factor, SOX9, is expressed by melanocytes in neonatal and adult human skin and is up-regulated by UVB exposure. We demonstrate that this regulation is mediated by cAMP and protein kinase. We also show that agouti signal protein, a secreted factor known to decrease pigmentation, down-regulates SOX9 expression. In adult and neonatal melanocytes, SOX9 regulates microphthalmia-associated transcription factor, dopachrome tautomerase, and tyrosinase promoters, leading to an increase in the expression of these key melanogenic proteins and finally to a stimulation of pigmentation. SOX9 completes the complex and tightly regulated process leading to the production of melanin by acting at a very upstream level. This role of SOX9 in pigmentation emphasizes the poorly understood impact of SOX proteins in adult tissues.microphthalmia-associated transcription factor ͉ tyrosinase ͉ protein kinase A ͉ melanocyte-stimulating hormone ͉ agouti signal protein S ox (SRY type HMG box) proteins are transcription factors that belong to the HMG box superfamily of DNA-binding proteins and play a key role during development. SOX9 belongs to the SOX-E subgroup, which includes SOX8, SOX9, and SOX10. The structures of these proteins show a high conservation and similar positions of their HMG boxes (1). SOX10 has been shown to play a key role in the regulation of melanocyte differentiation (2), and mutations in SOX10 lead to Waardenburg syndrome type 4, a genetic hypomelanosis with deafness and megacolon (3). During melanocyte development from the neural crest, SOX10 regulates the expression of microphthalmia-associated transcription factor (MITF), which in turn controls a set of genes critical for pigment cell development and pigmentation (4). Indeed, in conjunction with other transcription factors, MITF regulates dopachrome tautomerase (DCT), tyrosinase (the limiting enzyme for melanogenesis), and tyrosinase-related protein 1 (TYRP1). All of these proteins are essential for the full differentiation of melanocytes and are directly involved in melanin synthesis. SOX10 also acts as a critical transactivator of DCT, which MITF, on its own, is insufficient to stimulate (5-7).SOX9 has a key role in sexual determination and chondrogenesis, and mutations in SOX9 can lead to campomelic dysplasia, a skeletal dysmorphology associated in most XY cases with sex reversal (8, 9). During embryonic development, the SOX9 gene becomes active in all prechondrocytic mesenchymal condensations, and its expression is maintained at high levels in fully differentiated chondrocytes. The direct target for SOX9 is a chondrocyte-specific enhancer in the gene for collagen ...

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Involvement of Microphthalmia in the Inhibition of Melanocyte Lineage Differentiation and of Melanogenesis by Agouti Signal Protein

Cited by 174 publications

References 44 publications

Microarray analysis sheds light on the dedifferentiating role of agouti signal protein in murine melanocytes via the Mc1r

Microarray analysis sheds light on the dedifferentiating role of agouti signal protein in murine melanocytes via the Mc1r

Cyclic AMP a Key Messenger in the Regulation of Skin Pigmentation

SOX9 is a key player in ultraviolet B-induced melanocyte differentiation and pigmentation

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