MITF (microphthalmia-associated transcription factor)

2013-04-01   Nicole D Riddle , Paul Zhang 

Department of Pathology, University of Texas Health Science Center, San Antonio, TX, USA (NDR); Department of Pathology, University of Pennsylvania Health System, Philadelphia, PA, USA (PZ)


Atlas Image



The gene encompasses 229 kb, and has 9 exons.


Nine different isoforms have been described for MITF, each with different 5 specificity (MITF -A, -J, -C, -MC, -E, -H, -D, -B, -M). All isoforms have exons 2-9 in common, encoding the functional domains of the transcription factors. Exon 1 is variable and the domains within it are the transactivation domain (TAD) and the beta-helix-loop-helix-zipper (B-HLH-Zip). Some isoforms are specific for certain cells types, i.e. M: melanocytes, MC: mast cells (Levy et al., 2006).



526 aa, 58795 Da.
Regulates the differentiation and development of melanocytes, neural crest-derived cells, retinal epithelium (optic cup-derived retinal pigment epithelium), mast cells, and osteoclasts (Lin and Fisher, 2007; Adijanto et al., 2012).

Post translational modifications:
- Phosphorylation at Ser-405 significantly enhances the ability to bind the tyrosinase promoter.
- Phosphorylation at Ser-180 and Ser-516 by MAPK and RPS6KA1 activate the transcription factor activity and promote ubiquitiniation and subsequent degradation.
- Can be deubiquitinated by USP13, preventing its degradation.


Found in most human tissues. Particularly high quantities in retina, uterus, pineal gland, and adipocytes (




A transcription factor that activates the transcription of tyrosinase and tyrosinase-related protein 1 (TYRP1), and dopachrome tautomerase (DCT). These are enzymes that are specifically expressed in melanocytes (Yasumoto et al., 1995). For tyrosinase, MITF binds to a symmetrical DNA sequence found in the promoter region: a restricted subset of E-box motives containing canonical CATGTG sequence flanked by a 5 thymidine (Aksan and Goding, 1998). The regulation of the DCT promoter is even more complex and involves other proteins like CREB and SOX10; and PAX3 has an inhibitory effect on DCT activation by MITF (Bertolotto et al., 1998; Ludwig et al., 2004; Lang et al., 2005).
Not only does MITF activate genes involved in melanin synthesis, it also activates the transcription of genes involved in melanosome structure (PMEL17, MART-1), biogenesis (ocular albinism type 1 gene), and transport (RAB27A) (Du et al., 2003; Vetrini et al., 2004; Chiaverini et al., 2008). Also, MITF activates the transcription of the melanocortin 1 receptor gene which encodes a melanocyte-stimulating hormone receptor normally present on the plasma membrane of melanocytes: this binding is the first step in the hormonal regulation of pigmentation (Vachtenheim and Borovansky, 2010).
In addition, MITF plays a role in apoptosis through several target genes, showing importance of MITF in melanocyte development and survival. MITF controls the transcription of BCL-2, and known inhibitor of apoptosis (McGill et al., 2002). Therefore, MITF mutation may explain the reduced number of melanocytes in certain disorders (Samija et al., 2010). MITF also induces transcription of melanoma-inhibitor-of-apoptosis (BIRC7, ML-IAP) (Dynek et al., 2008). Furthermore, it regulates a receptor for hepatocyte growth factor (MET), whose activation inhibits melanocyte apoptosis (Beuret et al., 2007).
MITF also plays a role in melanocyte proliferation by regulating several genes involved in the cell-cycle: cyclin-dependant kinase 2 (CDK2), transcription factor TBX2, and Dia1 protein (Diaph1). These promote cell-cycle progression, prevent senescence and cell-cycle arrest, and increase cellular proliferation, respectively (Du et al., 2004; Carreira et al., 2005; Carreira et al., 2006). However, MITF also has anti-proliferative properties by way of inducing cell-cycle arrest by activating cyclin-dependent kinase inhibitor 1A and 2A (CDKN1A/p21, CDKN2A/p16) (Carreira et al., 2005; Loercher et al., 2005). It has believed that both depletion and over-expression inhibit proliferation whereas normal levels promote proliferation (Kido et al., 2009).
MITF also has important roles in osteoclast and mast cell development and function. In osteoclasts it activates transcription of functional proteins tartrate-resistant alkaline phosphatase (TRAP), cathepsin K, OSCAR, e-cadherin, OSTM1 and CLCN7 (Meadows et al., 2007). In mast cells MITF activates the transcription of mast cell proteases 2,4,5,6, and 9, granzyme B, tryptophan hydroxylase, and kit, all important for differentiation and function (Kitamura et al., 2006).
Up-stream regulation: LysRS-Ap4A-MITF signaling pathway (Lee et al., 2004); Wnt signaling pathway (Takeda et al., 2000); alpha melanocyte-stimulating hormone signaling pathway (Bertolotto et al., 1998).


High homology to TFE genes (TFE3, TFEB, TFEC, etc.) and the myc family of bHLH transcription factors (Dickson et al., 2011).



The MITF promoter is partially regulated by certain transcription factors such as PAX3, SOX10, LEF-1/TCF and CREB during development. Mutations affecting the MITF and the MITF pathway lead to pigmentary and auditory defects (Cimadamore et al., 2012; Pierrat et al., 2012).


Mutations in the MITF at germline will lead to syndromes with pigmentary and/or auditory defects. Mutations in MITF are also known to give a predisposition to certain cancers, including melanoma and renal cell carcinoma (Bertolotto et al., 2011). Heterozygous mutations lead to auditory/pigmentary syndromes such as Waardenburg type 2 and Tietz syndrome (Lin and Fisher, 2007).

Implicated in

Entity name
A malignant neoplasm of melanocytes, arising either from pre-existing benign nevi or de novo and occurring most commonly on the skin, but may occur in other locations.
In addition, BRAF mutations (found in ~60% of melanomas) have a two-fold regulation of MITF transcription and is believed to keep MITF at appropriate levels promoting melanoma cell proliferation and survival. Supporting this theory is the fact that pure up-regulation of MITF inhibits melanoma cell proliferation and re-expression reduces tumorigenecity in vivo (Wellbrock and Marais, 2005). And MITF expression by immunohistochemistry has been shown to decrease with disease progression, and be a predictor of overall and disease-free survival (Salti et al., 2000; Zhuang et al., 2007).
MITF amplification has also been associated with decreased survival and chemoresistance (Gallaway et al., 2005). It is postulated the MITF may be a lineage specific oncogene in melanoma, particularly in the subset with CDKN2A mutations (Garraway and Sellers, 2006; Bennett, 2008). This hypothesis is supported by research that has shown that all melanoma cell lines that had MITF gene amplifications also had CDKN2A pathway inactivation (Gallaway et al., 2005). MITFs role as a lineage specific oncogene is also supported by its important part in cell growth, survival, growth, and proliferation through BCL2, CDK2, TBX2, ML-IAP etc, as described above.
As mentioned above, MITF is not expressed in all melanomas. This indicates that there are different subsets of melanomas which differ in their need of MITF for their progression and survival (Salti et al., 2000; Miettinen et al., 2001; Granter et al., 2002). There is also evidences that the role of MITF may change within a melanoma during progression (Hoek et al., 2008a).
Entity name
Renal cell carcinoma
Malignant transformation of the renal parenchyma. Associated with Von Hippel-Lindau syndrome: a rare, autosomal dominant disease predisposing to clear cell renal cell carcinoma, as well as hemangioblastomas, pheochromocytomas, pancreatic cysts and neuroendocrine tumors, endolymphatic sac tumors, and a general increase risk in cancer; results from mutation of the VHL tumor suppressor gene on chromosome 3p.
A subset of renal cell carcinomas, more common in children, are associated with TFE3 mutations, a member of the microphthalmia (MIT) family, closely related to MITF.
Recent studies have shown that the same MITF mutation associated with increased risk of melanoma (E318K) also leads to increased risk of renal cell carcinoma (Bertolotto et al., 2011). However, it is unclear at this time the role that MITF in particular plays in renal tumors. It may be that this mutation leads to disrupted interaction with TFE3. Or it is possible that mechanisms are similar to that of melanoma, however, MITF is not associated with normal kidney function in the same way that it is in normal melanocyte function. Research is ongoing in this area.
Entity name
Waardenburg syndrome
A group of autosomal dominant inherited conditions that involve deafness and lack of pigment of the hair, skin, and/or eyes. There are 4 main types of WS, 1 and 2 being most common. MITF is the gene associated with Waardenburg syndrome 2a (WS2a), characterized by sensorineural hearing loss and patches of depigmentation, with or without ocular albinism. These features may show variable expression and penetrance.
Some of the mutations are single or multiple amino acid changes that alter the helix-loop-helix or leucine zipper motif. There are other mutations that create a shortened, non-functional version of MITF. It is believed that all of these mutations disrupt the formation of the dimers necessary for proper function and development; thereby there is an insufficient concentration of the MITF protein within the cytoplasm for normal function (haploinsufficiency). Also, as described above, MITF regulates BCL-2, ML-IAP, and MET. Without adequate amounts of MITF there is over-apoptosis of melanocytes. This leads to a decreased number of melanocytes in certain areas of the skin, hair, eyes, inner ear, etc (Tachibana, 1997; Samija et al., 2010).
Patients with WS1 will have the addition of craniofacial deformities and those with WS3 (Klein-Waardenburg syndrome) have limb deformities, both are due to mutations in PAX3, which is part of the MITF pathway, Those with WS4 (Waardenburg-Shah Syndrome) will also have Hirchsprungs syndrome, associated with mutations in 3 genes: SOX10, endothelin 3, and endothelin receptor B (Tassabehji et al., 1995; Widlund and Fisher, 2003).
Entity name
Tietz syndrome
An autosomal dominant disorder characterized by generalized hypopigmentation (fair skin and light-colored hair) and profound bilateral congenital hearing loss. Penetrance is complete.
The mutation is a change or deletion of a single amino acid in the basic motif region. This resultant altered protein cannot bind to DNA, thereby affecting the development of melanocytes, and therefore, melanin production (Smith et al., 2000). The mechanism is similar to Waardenburg syndrome, but more severe. In a heterozygote the abnormal protein cannot dimerise effectively even with a normal allele product, i.e. even the normal allele does not function. This concept is referred to as a dominant negative. There is effectively no normal MITF available (Smith et al., 2000).


Pubmed IDLast YearTitleAuthors
225230782012Microphthalmia-associated transcription factor (MITF) promotes differentiation of human retinal pigment epithelium (RPE) by regulating microRNAs-204/211 expression.Adijanto J et al
98193811998Targeting the microphthalmia basic helix-loop-helix-leucine zipper transcription factor to a subset of E-box elements in vitro and in vivo.Aksan I et al
183531412008How to make a melanoma: what do we know of the primary clonal events?Bennett DC et al
220122592011A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma.Bertolotto C et al
173718762007Up-regulation of MET expression by alpha-melanocyte-stimulating hormone and MITF allows hepatocyte growth factor to protect melanocytes and melanoma cells from apoptosis.Beuret L et al
195783642009Genome-wide association study identifies three loci associated with melanoma risk.Bishop DT et al
171828682006Mitf regulation of Dia1 controls melanoma proliferation and invasiveness.Carreira S et al
182812842008Microphthalmia-associated transcription factor regulates RAB27A gene expression and controls melanosome transport.Chiaverini C et al
225714032012SOX2 modulates levels of MITF in normal human melanocytes, and melanoma lines in vitro.Cimadamore F et al
194226062009Frequent mutations in the MITF pathway in melanoma.Cronin JC et al
201640562011TFE3 expression in tumors of the microphthalmia-associated transcription factor (MiTF) family.Dickson BC et al
128190382003MLANA/MART1 and SILV/PMEL17/GP100 are transcriptionally regulated by MITF in melanocytes and melanoma.Du J et al
156079612004Critical role of CDK2 for melanoma growth linked to its melanocyte-specific transcriptional regulation by MITF.Du J et al
184511372008Microphthalmia-associated transcription factor is a critical transcriptional regulator of melanoma inhibitor of apoptosis in melanomas.Dynek JN et al
168621902006Lineage dependency and lineage-survival oncogenes in human cancer.Garraway LA et al
226473782012The tumor suppressor HINT1 regulates MITF and β-catenin transcriptional activity in melanoma cells.Genovese G et al
128442862003Localization of a novel melanoma susceptibility locus to 1p22.Gillanders E et al
118930352002Role for microphthalmia transcription factor in the diagnosis of metastatic malignant melanoma.Granter SR et al
182454632008In vivo switching of human melanoma cells between proliferative and invasive states.Hoek KS et al
190679712008Novel MITF targets identified using a two-step DNA microarray strategy.Hoek KS et al
196596112009Simultaneous suppression of MITF and BRAF V600E enhanced inhibition of melanoma cell proliferation.Kido K et al
169312852006Molecular mechanisms of mast cell development.Kitamura Y et al
157293462005Pax3 functions at a nodal point in melanocyte stem cell differentiation.Lang D et al
149752372004The function of lysyl-tRNA synthetase and Ap4A as signaling regulators of MITF activity in FcepsilonRI-activated mast cells.Lee YN et al
168994072006MITF: master regulator of melanocyte development and melanoma oncogene.Levy C et al
173149702007Melanocyte biology and skin pigmentation.Lin JY et al
156235832005MITF links differentiation with cell cycle arrest in melanocytes by transcriptional activation of INK4A.Loercher AE et al
147068562004Melanocyte-specific expression of dopachrome tautomerase is dependent on synergistic gene activation by the Sox10 and Mitf transcription factors.Ludwig A et al
120866702002Bcl2 regulation by the melanocyte master regulator Mitf modulates lineage survival and melanoma cell viability.McGill GG et al
171057302007The expression of Clcn7 and Ostm1 in osteoclasts is coregulated by microphthalmia transcription factor.Meadows NA et al
111760692001Microphthalmia transcription factor in the immunohistochemical diagnosis of metastatic melanoma: comparison with four other melanoma markers.Miettinen M et al
224964492012Expression of microphthalmia-associated transcription factor (MITF), which is critical for melanoma progression, is inhibited by both transcription factor GLI2 and transforming growth factor-β.Pierrat MJ et al
110166202000Micropthalmia transcription factor: a new prognostic marker in intermediate-thickness cutaneous malignant melanoma.Salti GI et al
108512562000Tietz syndrome (hypopigmentation/deafness) caused by mutation of MITF.Smith SD et al
91701591997Evidence to suggest that expression of MITF induces melanocyte differentiation and haploinsufficiency of MITF causes Waardenburg syndrome type 2A.Tachibana M et al
107478532000Induction of melanocyte-specific microphthalmia-associated transcription factor by Wnt-3a.Takeda K et al
85896911995The mutational spectrum in Waardenburg syndrome.Tassabehji M et al
107605822000Structural organization of the human microphthalmia-associated transcription factor gene containing four alternative promoters.Udono T et al
202019542010"Transcription physiology" of pigment formation in melanocytes: central role of MITF.Vachtenheim J et al
157816392005Tbx2 is overexpressed and plays an important role in maintaining proliferation and suppression of senescence in melanomas.Vance KW et al
152542232004The microphthalmia transcription factor (Mitf) controls expression of the ocular albinism type 1 gene: link between melanin synthesis and melanosome biogenesis.Vetrini F et al
182872842008Intersubunit linker length as a modifier of protein stability: crystal structures and thermostability of mutant TRAP.Watanabe M et al
161297812005Elevated expression of MITF counteracts B-RAF-stimulated melanocyte and melanoma cell proliferation.Wellbrock C et al
127892782003Microphthalamia-associated transcription factor: a critical regulator of pigment cell development and survival.Widlund HR et al
87493021995Transcriptional activation of the melanocyte-specific genes by the human homolog of the mouse Microphthalmia protein.Yasumoto K et al
220809502011A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma.Yokoyama S et al
173846502007Mcl-1, Bcl-XL and Stat3 expression are associated with progression of melanoma whereas Bcl-2, AP-2 and MITF levels decrease during progression of melanoma.Zhuang L et al

Other Information

Locus ID:

NCBI: 4286
MIM: 156845
HGNC: 7105
Ensembl: ENSG00000187098


dbSNP: 4286
ClinVar: 4286
TCGA: ENSG00000187098


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Pathways in cancerKEGGhsa05200
Osteoclast differentiationKEGGko04380
Osteoclast differentiationKEGGhsa04380
Metabolism of proteinsREACTOMER-HSA-392499
Post-translational protein modificationREACTOMER-HSA-597592
SUMO E3 ligases SUMOylate target proteinsREACTOMER-HSA-3108232
SUMOylation of transcription factorsREACTOMER-HSA-3232118
Mitophagy - animalKEGGko04137
Mitophagy - animalKEGGhsa04137

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
160010722005Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma.482
234778302013Oncogenic BRAF regulates oxidative metabolism via PGC1α and MITF.263
191885902009Aberrant miR-182 expression promotes melanoma metastasis by repressing FOXO3 and microphthalmia-associated transcription factor.216
120866702002Bcl2 regulation by the melanocyte master regulator Mitf modulates lineage survival and melanoma cell viability.193
171828682006Mitf regulation of Dia1 controls melanoma proliferation and invasiveness.182
247718462014A melanoma cell state distinction influences sensitivity to MAPK pathway inhibitors.157
255021422014Low MITF/AXL ratio predicts early resistance to multiple targeted drugs in melanoma.148
220122592011A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma.138
220809502011A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma.125
186289672008Oncogenic BRAF regulates melanoma proliferation through the lineage specific factor MITF.98


Nicole D Riddle ; Paul Zhang

MITF (microphthalmia-associated transcription factor)

Atlas Genet Cytogenet Oncol Haematol. 2013-04-01

Online version: