MITF: Master regulator of melanocyte development and melanoma oncogene
ABSTRACT 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.
- SourceAvailable from: Olalekan A Ayo-Yusuf
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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  and is responsible for modulating expression of some melanocyte-specific proteins . Following differentiation of melanocytes, MITF regulates expression of genes during exposure to UVR, thus assisting in tanning of the skin . "
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.09/2015; 2015:167847. DOI:10.1155/2015/167847
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- "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). "
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.Journal of Cellular Physiology 07/2015; DOI:10.1002/jcp.25108 · 3.84 Impact Factor
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- "Also, the gene coding for microphthalmia-associated transcription factor (MITF) was highly differentially expressed. The latter is the key regulator of melanocytes and melanoma cells and DCT and TYR are targets of MITF (Levy et al., 2006). Endothelin receptor type B (EDNRB) was also highly up-regulated. "
ABSTRACT: Motivation: Understanding regulation of transcription is central for elucidating cellular regulation. Several statistical and mechanistic models have come up the last couple of years explaining gene transcription levels using information of potential transcriptional regulators as transcription factors (TFs) and information from epigenetic modifications. The activity of TFs is often inferred by their transcription levels, promoter binding and epigenetic effects. However, in principle, these methods do not take hard-to-measure influences such as post-transcriptional modifications into account. Results: For TFs, we present a novel concept circumventing this problem. We estimate the regulatory activity of TFs using their cumulative effects on their target genes. We established our model using expression data of 59 cell lines from the National Cancer Institute. The trained model was applied to an independent expression dataset of melanoma cells yielding excellent expression predictions and elucidated regulation of melanogenesis. Availability and implementation: Using mixed-integer linear programming, we implemented a switch-like optimization enabling a constrained but optimal selection of TFs and optimal model selection estimating their effects. The method is generic and can also be applied to further regulators of transcription. Contact: firstname.lastname@example.org Supplementary information: Supplementary data are available at Bioinformatics online.08/2014; 30(17-17):i401-i407. DOI:10.1093/bioinformatics/btu446