MITF: Master regulator of melanocyte development and melanoma oncogene

Melanoma Program and Department of Pediatric Hematology and Oncology, Dana-Farber Cancer Institute, Children's Hospital Boston, 44 Binney Street, Boston, MA 02115, USA.
Trends in Molecular Medicine (Impact Factor: 9.45). 10/2006; 12(9):406-14. DOI: 10.1016/j.molmed.2006.07.008
Source: PubMed


Microphthalmia-associated transcription factor (MITF) acts as a master regulator of melanocyte development, function and survival by modulating various differentiation and cell-cycle progression genes. It has been demonstrated that MITF is an amplified oncogene in a fraction of human melanomas and that it also has an oncogenic role in human clear cell sarcoma. However, MITF also modulates the state of melanocyte differentiation. Several closely related transcription factors also function as translocated oncogenes in various human malignancies. These data place MITF between instructing melanocytes towards terminal differentiation and/or pigmentation and, alternatively, promoting malignant behavior. In this review, we survey the roles of MITF as a master lineage regulator in melanocyte development and its emerging activities in malignancy. Understanding the molecular function of MITF and its associated pathways will hopefully shed light on strategies for improving therapeutic approaches for these diseases.

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    • "A number of genes control the proliferation and differentiation of neural crest cells and also regulate the migration of precursor melanocytes to their ultimate positions in the skin and eye. Microphthalmia transcription factor (MITF) is the master regulator of melanocyte development, function, and survival [4] and is responsible for modulating expression of some melanocyte-specific proteins [5]. Following differentiation of melanocytes, MITF regulates expression of genes during exposure to UVR, thus assisting in tanning of the skin [6]. "
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    ABSTRACT: Oculocutaneous albinism which is characterised by impaired melanin biosynthesis is the most common inherited pigmentary disorder of the skin and it is common among Blacks in sub-Saharan Africa. All albinos are at great risk of developing squamous cell carcinoma of sun-exposed skin, and Black albinos in sub-Saharan Africa are at about a 1000-fold higher risk of developing squamous cell carcinoma of the skin than the general population. In Black albinos, skin carcinoma tends to run an aggressive course and is likely to recur after treatment, very probably because the aetiology and predisposing factors have not changed. Prevention or reduction of occurrence of squamous cell carcinoma of the skin in Black albinos might be achieved through educating the population to increase awareness of the harmful effects of exposure to sunlight and at the same time making available effective screening programs for early detection of premalignant and malignant skin lesions in schools and communities and for early treatment.
    Full-text · Article · Sep 2015
    • "One downstream effector which integrates these two signaling pathways to induce the transcription of genes necessary for osteoclast function is the microphthalmia-associated transcription factor, MITF, a basic-helix-loop-helix leucine zipper (bHLHZip) family transcription factor (Hodgkinson et al., 1993). MITF is most well known as the master regulator of the melanin producing melanocyte linage and as an oncogene in melanomas (Hemesath et al., 1994; Levy et al., 2006). However, it also plays important roles in the transcriptional regulation of genes in other diverse cell types including retinal pigmented epithelial cells of the eye, mast cells of the innate immune system, and bone resorbing osteoclasts (Moore, 1995). "
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    ABSTRACT: The microphthalmia-associated transcription factor (MITF) is a basic helix-loop-helix leucine zipper family factor that is essential for terminal osteoclast differentiation. Previous work demonstrates that phosphorylation of MITF by p38 MAPK downstream of receptor activator of NFκB ligand (RANKL) signaling is necessary for MITF activation in osteoclasts. The spontaneous Mitf cloudy eyed (ce) allele results in production of a truncated MITF protein that lacks the leucine zipper and C-terminal end. Here we show that the Mitf(ce) allele leads to a dense bone phenotype in neonatal mice due to defective osteoclast differentiation. In response to RANKL stimulation, in vitro osteoclast differentiation was impaired in myeloid precursors derived from neonatal or adult Mitf(ce/ce) mice. The loss of the leucine zipper domain in Mitf(ce/ce) mice does not interfere with the recruitment of MITF/PU.1 complexes to target promoters. Further, we have mapped the p38 MAPK docking site within the region deleted in Mitf(ce) . This interaction is necessary for the phosphorylation of MITF by p38 MAPK. Site-directed mutations in the docking site interfered with the interaction between MITF and its co-factors FUS and BRG1. MITF-ce fails to recruit FUS and BRG1 to target genes, resulting in decreased expression of target genes and impaired osteoclast function. These results highlight the crucial role of signaling dependent MITF/ p38 MAPK interactions in osteoclast differentiation. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    No preview · Article · Jul 2015 · Journal of Cellular Physiology
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    • "Among them, tyrosinase plays two important rate-limiting steps during melanin biosynthesis (Hearing and Jimenez, 1987). The tyrosinase family genes TRP-1 and TRP-2 are transcriptionally regulated by microphatalmia-associated transcription factor (MITF), which suggests that MITF is an important transcription regulator during melanogenesis (Tachibana, 2001; Levy et al., 2006; Ye et al., 2010; Tsang et al., 2012). Previously, researchers have documented that mitogen-activated protein kinases (MAPKs) consist of a family of serine/threonine kinases, including p38 MAPK, extracellular response kinase (ERK), and "
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    ABSTRACT: In this study, the effect of purified Quercetin-3-O-β-D-Glucopyranosyl-(1→6)-β-D-Glucopyranosid (QCGG) on melanogenesis was investigated. QCGG was isolated from the calyx of a traditional Korean medicinal herb, Persimmon (Diospyros kaki). The hypopigmentation effects of QCGG were determined by examination of cellular melanin contents, tyrosinase activity assay, cAMP assay, and Western blotting of α-MSH-stimulated B16F10 mouse melanoma cells. Our results showed that QCGG inhibited both melanin synthesis and tyrosinase activity in a concentration-dependent manner as well as significantly reduced the expression of melanogenic proteins such as microphthalmia-associated transcription factor (MITF), tyrosinase-related protein-1, tyrosinase-related protein-2, and tyrosinase. Moreover, QCGG inhibited intracellular cAMP levels, cAMP response element-binding protein (CREB), and p38 MAPK expression in α-MSH-stimulated B16F10 cells. Taken together, the suppressive effects of QCGG on melanogenesis may involve down-regulation of MITF and its downstream signaling pathway via phosphorylation of p38 MAPK and CREB along with reduced cAMP levels. These results indicate that QCGG reduced melanin synthesis by reducing expression of tyrosine and tyrosine-related proteins via extracellular signal-related protein kinase (ERK) activation, followed by down-regulation of CREB, p38, and MITF.
    Full-text · Article · Mar 2015 · Saudi Journal of Biological Sciences
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