MITF

Official Full Name

melanocyte inducing transcription factor

Organism

Homo sapiens

GeneID

4286

Background

The protein encoded by this gene is a transcription factor that contains both basic helix-loop-helix and leucine zipper structural features. The encoded protein regulates melanocyte development and is responsible for pigment cell-specific transcription of the melanogenesis enzyme genes. Heterozygous mutations in the this gene cause auditory-pigmentary syndromes, such as Waardenburg syndrome type 2 and Tietz syndrome. [provided by RefSeq, Aug 2017]

Synonyms

MI; WS2; CMM8; WS2A; COMMAD; MITF-A; bHLHe32;

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Detailed Information

The small eye deformity-related transcription factor (MITF) is a transcription factor with a typical helix-loop-helix-leucine zipper structure. It has been found to exist in many species and participate in the growth, development, differentiation and functional regulation of organisms. The study found that MITF is mainly expressed in pigment cells, including melanoblasts and retinal pigment epithelium (RPE). It is also expressed in other cells, such as mast cells and osteoclasts. Mutations in the MITF gene cause a series of phenotypic changes in many species, especially in pigment cells, where some mutations can affect RPE, leading to pigmentation, hypothyroidism, and small eye deformities in the eye. Loss of human MITF gene expression causes the Waardenburg syndrome type II. This type of patient presents with congenital cataracts and neurological deafness. There are also a few MITF alleles that can cause bone sclerosis by affecting osteoclasts.

MITF Figure 1. Model portraying a positive feedback loop involving MITF, MVBs, and Wnt signaling in proliferative stages of melanoma. (Ploper, D., et al. 2015)

Expression of MITF in Melanoma

In different biological stages of melanoma cell senescence, apoptosis, proliferation and migration, MITF is involved in regulating the expression of different genes. Studies have found that protein kinase-mediated phosphorylation of MITF increases affinity with tumor protein 53 and promotes cell senescence. B cell lymphoma factor 2 is the first confirmed anti-apoptotic target gene of MITF, and its family member B cell lymphoma factor 2A1 is an important regulatory molecule for the anti-apoptotic function of MITF, which is in about 30% of melanoma cells. It is expressed that by up-regulating B-cell lymphoma factor 2A1, MITF exerts an anti-apoptotic effect. The T-box transcription factor encoding gene is the first target gene for proliferative properties of MITF, and plays a role in promoting proliferation and anti-aging by up-regulating the T-box transcription factor-encoding gene. Genes involved in melanoma infiltration, such as insulin-like growth factor binding protein 5 antibody, serine-combined protein 3 antibody, and transcription factor-specificity determining region Y-box protein, are also regulated by MITF.

Metastasis of MITF and Melanoma

Studies have shown that miR-221 exhibits low expression in melanoma cells to promote migration. miR-221 is located in the intron of the transient receptor potential M subunit 1. MITF regulates the expression level of miR-221 itself and also affects the expression of the transient receptor M subunit 1. In a study of clinical stage IV melanoma patients, miR-101 was found to act by inhibiting invasion, migration, and proliferation in melanoma cells by directly acting on MITF and histone methylation transferase, while miR- 101 is also associated with prognosis and is a prognostic factor. The study found that MITF can activate the migration of melanoma cells in synergy with miR-340. MITF can be used as an upstream regulatory molecule of miRNA or as a downstream target gene involved in the regulation of metastasis, mainly as a low expression of MITF to promote metastasis.

In the melanoma cells Mull with low expression of β-catenin and moderate expression of MITF, it was found that the β-catenin-regulated MITF can reduce the migration of melanoma cells by cell migration rate, Western blotting and immunofluorescence assay. In addition, studies have found that the secretion of frizzled-related protein 2 produced by fibroblasts promotes the decreased expression of β-catenin and MITF, which ultimately leads to the loss of expression of apyrimidine endonuclease and the increased metastatic ability of melanoma.

References:

Ploper, D. , & De Robertis, E. M. . (2015). The mitf family of transcription factors: role in endolysosomal biogenesis, wnt signaling, and oncogenesis. Pharmacological Research the Official Journal of the Italian Pharmacological Society, 99, 36-43.
Grill, C. , Bergsteinsdottir, K. , Ogmundsdottir, M. H. , Pogenberg, V. , Schepsky, A. , & Wilmanns, M. , et al. (2013). Mitf mutations associated with pigment deficiency syndromes and melanoma have different effects on protein function. Human Molecular Genetics, 22(21), 4357-4367.
Harris, M. L. , Fufa, T. D. , Palmer, J. W. , Joshi, S. S. , Larson, D. M. , & Arturo, I. , et al. (2018). A direct link between mitf, innate immunity, and hair graying. PLOS Biology, 16(5), e2003648.

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