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During melanocyte development, the cytokine Steel factor activates its receptor c-Kit, initiating a signal transduction cascade, which is vital for lineage determination via unknown downstream nuclear targets. c-Kit has recently been found to trigger mitogen-activated protein kinase-mediated phosphorylation of Microphthalmia (Mi), a lineage-restricted transcription factor, which, like Steel factor and c-Kit, is essential for melanocyte development. This cascade results in increased Mi-dependent transcriptional reporter activity. Here we examine the mechanism by which Mi is activated by this pathway. Phosphorylation does not significantly alter Mi's nuclear localization, DNA binding, or dimerization. However, the transcriptional coactivator p300/CBP selectively associates with mitogen-activated protein kinase-phosphorylated Mi, even under conditions in which non-MAPK phospho-Mi is more abundant. Moreover, p300/CBP coactivates Mi transcriptional activity in a manner dependent upon this phosphorylation. Mi thus joins CREB as a transcription factor whose signalresponsive phosphorylation regulates coactivator recruitment, in this case modulating lineage development in melanocytes.Mutations in the genes that encode the receptor tyrosine kinase c-Kit (1), its ligand Steel factor (Sl, mast/stem cell growth factor) (2, 3), and the basic/helix-loop-helix/leucine zipper transcription factor Microphthalmia (Mi) 1 (4) all produce severe melanocyte deficiency in mouse. This striking phenotypic overlap has led to the suggestion that Sl, c-Kit, and Mi function in a common growth/differentiation pathway (5, 6). In human, c-Kit mutation is associated with patchy depigmentation called piebaldism (7), and Mi mutation causes Waardenburg Syndrome type II marked by depigmentation and deafness because of pigment cell deficiency in the skin and inner ear (8). Mi has been shown to modulate c-Kit expression levels in mast cells (6). Recent studies have also biochemically linked Mi to the c-Kit signaling pathway (9). In response to Sl stimulation, c-Kit signaling activates MAP kinase (MAPK/Erk), which directly phosphorylates Mi at serine 73 (Ser-73), based on two-dimensional tryptic analyses of in vitro and in vivo phosphorylated Mi protein (9). This phosphorylation is associated with increased expression of a reporter driven by the tyrosinase pigmentation gene promoter.Mi is a highly tissue-restricted dimeric transcription factor, which recognizes "E box"-containing promoter/enhancer elements (4, 10 -12). Among its transcriptional targets are the melanocyte-specific tyrosine-metabolizing enzyme genes involved in melanin biosynthesis. In addition to the phenotypic similarity of c-Kit, Sl, and Mi mutant mice, recent clinical use of recombinant Sl in humans has demonstrated both proliferative and pigmentation responses in melanocytes near the injection site (13). These observations suggest that c-Kit signaling proceeds through regulated activation of Microphthalmia, which in turn initiates the pigmentation program and activates unknown genes...
During melanocyte development, the cytokine Steel factor activates its receptor c-Kit, initiating a signal transduction cascade, which is vital for lineage determination via unknown downstream nuclear targets. c-Kit has recently been found to trigger mitogen-activated protein kinase-mediated phosphorylation of Microphthalmia (Mi), a lineage-restricted transcription factor, which, like Steel factor and c-Kit, is essential for melanocyte development. This cascade results in increased Mi-dependent transcriptional reporter activity. Here we examine the mechanism by which Mi is activated by this pathway. Phosphorylation does not significantly alter Mi's nuclear localization, DNA binding, or dimerization. However, the transcriptional coactivator p300/CBP selectively associates with mitogen-activated protein kinase-phosphorylated Mi, even under conditions in which non-MAPK phospho-Mi is more abundant. Moreover, p300/CBP coactivates Mi transcriptional activity in a manner dependent upon this phosphorylation. Mi thus joins CREB as a transcription factor whose signalresponsive phosphorylation regulates coactivator recruitment, in this case modulating lineage development in melanocytes.Mutations in the genes that encode the receptor tyrosine kinase c-Kit (1), its ligand Steel factor (Sl, mast/stem cell growth factor) (2, 3), and the basic/helix-loop-helix/leucine zipper transcription factor Microphthalmia (Mi) 1 (4) all produce severe melanocyte deficiency in mouse. This striking phenotypic overlap has led to the suggestion that Sl, c-Kit, and Mi function in a common growth/differentiation pathway (5, 6). In human, c-Kit mutation is associated with patchy depigmentation called piebaldism (7), and Mi mutation causes Waardenburg Syndrome type II marked by depigmentation and deafness because of pigment cell deficiency in the skin and inner ear (8). Mi has been shown to modulate c-Kit expression levels in mast cells (6). Recent studies have also biochemically linked Mi to the c-Kit signaling pathway (9). In response to Sl stimulation, c-Kit signaling activates MAP kinase (MAPK/Erk), which directly phosphorylates Mi at serine 73 (Ser-73), based on two-dimensional tryptic analyses of in vitro and in vivo phosphorylated Mi protein (9). This phosphorylation is associated with increased expression of a reporter driven by the tyrosinase pigmentation gene promoter.Mi is a highly tissue-restricted dimeric transcription factor, which recognizes "E box"-containing promoter/enhancer elements (4, 10 -12). Among its transcriptional targets are the melanocyte-specific tyrosine-metabolizing enzyme genes involved in melanin biosynthesis. In addition to the phenotypic similarity of c-Kit, Sl, and Mi mutant mice, recent clinical use of recombinant Sl in humans has demonstrated both proliferative and pigmentation responses in melanocytes near the injection site (13). These observations suggest that c-Kit signaling proceeds through regulated activation of Microphthalmia, which in turn initiates the pigmentation program and activates unknown genes...
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