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Microphthalmia-associated Transcription Factor (microphthalmia-associated + transcription_factor)

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Medical Sciences60%

Selected Abstracts

Fifteen-year quest for microphthalmia-associated transcription factor target genes

PIGMENT CELL & MELANOMA RESEARCH, Issue 1 2010
Yann Cheli
Summary Microphthalmia-associated transcription factor (MITF) was initially shown to play a key role in melanocyte differentiation through the direct transcriptional control of TYROSINASE, TYRP1 and DCT genes, encoding the three enzymes involved in melanin synthesis or melanogenesis. Sixteen years after the first description of MITF, more than 40 direct MITF target genes have been described. They play a key role in melanocyte, osteoclast and mast cell specific functions. Furthermore, several MITF target genes, e.g. BCL2, CDK2, CDKN1A, CDKN2A, MET and HIF1A, link MITF to general cellular processes such as growth or survival. In this review, we provide an overview of the MITF-regulated genes. We pay special attention to the MITF target genes in melanocytes and raise questions about target specificity. [source]

Long-term suppression of tyrosinase by terrein via tyrosinase degradation and its decreased expression

EXPERIMENTAL DERMATOLOGY, Issue 6 2009
Seo-Hyoung Park
Abstract:, Previously, we reported that a fungal metabolite, terrein, decreases melanin synthesis via downregulation of microphthalmia-associated transcription factor (MITF). In the present study, we further investigated the long-term hypopigmenting action of terrein in a spontaneously immortalized mouse melanocyte cell line, Mel-Ab. Treatment with terrein at a concentration of 50 ,m strongly decreased melanogenesis in a time-dependent manner. Interestingly, the decreased tyrosinase protein levels lasted for at least 7 days, even though the MITF protein levels were restored after 3 days of treatment. In accordance with the results of Western blot analyses, the tyrosinase mRNA levels were found to be continuously decreased for at least 7 days, even though recovery of the MITF mRNA levels began after 3 days of terrein treatment. Therefore, we evaluated tyrosinase downregulation to determine if it is caused by proteasomal degradation. We found that the reduction in tyrosinase levels that was induced by terrein was clearly recovered by MG-132, a proteasome inhibitor. Moreover, ubiquitination of tyrosinase increased following treatment with terrein in the presence of MG-132. Taken together, these results suggest that terrein decreases melanogenesis through ubiquitin-dependent proteasomal degradation as well as via decreased expression of its mRNA. [source]

,-MSH and cAMP signalling in normal human melanocytes

EXPERIMENTAL DERMATOLOGY, Issue 9 2004
R. Buscą
Melanocytes are neural crest-derived skin cells specialized in the synthesis of melanin pigments responsible, in human, for skin and hair colour. The pro-opiomelanocortin peptide, ,-MSH is a strong melanogenic agent secreted by keratinocytes following UV radiation. ,-MSH through the binding to the MC1R and activation of the cyclic AMP pathway plays a pivotal role in melanocyte differentiation and in the regulation of skin pigmentation. During the last few years, we have elucidated the molecular events linking the cAMP pathway to melanogenesis upregulation. This cascade involves the activation of protein kinase A and CREB transcription factor, leading to the upregulation of the expression of microphthalmia-associated transcription factor (MITF). MITF binds and activates the melanogenic gene promoters thereby increasing their expression, which results in an increased melanin synthesis. Beyond this simplified scheme, other intracellular signalling pathways are regulated by cAMP and participate to the regulation of melanocyte differentiation. Indeed, cAMP inhibits the phosphatidyl inositol 3-kinase pathway, leading to the inhibition of AKT and to the activation of GSK3,. This kinase phosphorylates MITF and allows its binding to the target sequence. Such pathways are involved in the upregulation of melanogenesis. ,-MSH and cAMP signalling also regulate melanocyte dendricity, and melanosome transport through the inhibition of the Rho GTPase cascade that function downstream the PI3 kinase. It should be also mentioned that cAMP activates the ERK pathway through a melanocyte-specific pathway involving Ras and B-Raf. The activation of ERK and RSK1 leads to the phosphorylation of MITF and target MITF to the proteasome degradation pathway. Interestingly, several proteins involved in melanocyte differentiation by ,-MSH (MC1R, PI3K, B-Raf and MITF) have also been implicated in the development of melanoma, suggesting that the cAMP pathway could influence melanocyte transformation. [source]

MITF-CM, a newly identified isoform of microphthalmia-associated transcription factor, is expressed in cultured mast cells

INTERNATIONAL JOURNAL OF LABORATORY HEMATOLOGY, Issue 2 2009
M. SHIOHARA
Summary The microphthalmia-associated transcription factor (MITF) gene encodes a basic helix-loop-helix and leucin zipper protein. In this study, we identified a novel MITF isoform, MITF-CM, which possesses a unique amino terminus. Exon 1CM is located 84 kb upstream of the exon encoding the B1b domain. MITF-CM was expressed in the human mast cell line HMC-1, the human basophilic cell line KU812, and CB-derived mast cells cultured for 10 weeks as well as bone marrow mononuclear cells. Transient transfection of MITF-CM cDNA in COS-7 cells resulted in the expression of a 64-kDa protein, detected by Western blotting, and nuclear localization of the protein, detected by immunostaining. The transient cotransfection of a luciferase construct under the control of the tyrosinase promoter and MITF-CM cDNA increased luciferase activity threefold. In contrast, none of the MITF isoforms transactivated both the tryptase and chymase gene promoters, indicating differences in the gene transactivation system between humans and mice. [source]

Molecular Bases of Congenital Hypopigmentary Disorders in Humans and Oculocutaneous Albinism 1 in Japan

PIGMENT CELL & MELANOMA RESEARCH, Issue 2000
YASUSHI TOMITA
The molecular bases of various types of congenital hypopigmentary disorders have been clarified in the past 10 years. Homozygous gene mutations of enzymes functional in melanogenesis such as tyrosinase, P protein and DHICA oxidase, result in oculocutaneous albinism (OCA) 1, OCA 2, and OCA 3, respectively. The genes responsible for Hermansky-Pudlak syndrome (HPS) and Chediak-Higashi syndrome (CHS) have also recently been isolated and cloned. The transcription factor paired box 3 (PAX3) works at the promoter region of the microphthalmia-associated transcription factor (MITF) gene, and the MITF transcription factor orders the expression of c-kit, which encodes the receptor for stem-cell factor, which in turn stimulates melanoblast migration from the neural tube to the skin in the embryo. Heterozygous mutations of PAX3, MITF, or c-kit genes induce Waardenburg syndrome (WS) 1/3, WS 2 or Piebaldism, respectively. A defect of endothelin-3 or the endothelin-B receptor produces WS 4. In our examination of 26 OCA 1 patients in Japan, all were found to have homozygous or heterozygous tyrosinase gene mutations at codons 77 or 310. Therefore, mutations at codons 77 and 310 are the major ones in Japanese patients with OCA 1. An autosomal dominant pigmentary disease of dyschromatosis symmetrica hereditaria (DSH) is well known in Japan, and is characterized by a mixture of hypo- and hyper-pigmented macules of various sizes on the backs of the hands and feet. The disease gene and its chromosomal localization have not been identified yet. Our trial of linkage analysis and positional cloning to determine the disease gene is presented. [source]