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Symbol MITF contributors: mct - updated : 03-09-2017
HGNC name microphthalmia-associated transcription factor
HGNC id 7105
Corresponding disease
ADFNS albinism-deafness syndrome, Tietz syndrome
COMMAD coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness
WS2A Waardenburg syndrome, type 2A
Location 3p14.1      Physical location : 69.788.585 - 70.017.488
Synonym name
  • homolog of mouse microphthalmia
  • class E basic helix-loop-helix protein 32
  • microphthalmia-associated transcription factor-M transcript
  • Synonym symbol(s) MI, bHLHe32
    TYPE functioning gene
    STRUCTURE 228.85 kb     10 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked N status confirmed
    TRANSCRIPTS type messenger
  • at least nine promoters driving expression of alternative first exons (PMID: 21949374)
  • identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    9 - 4472 46.8 419 melanocytes 2011 21949374
  • also called MITF-M or variant 4/isoform 4
  • exon 1M
  • key transcription factor for PKC-beta, linking the PKC- and cAMP-dependent pathways in regulation of melanogenesis
  • induced by TYRO3 in a SOX10-dependent manner in melanoma cells (Zhu 2009)
  • implicated in survival, proliferation, and differentiation of this neural crest-derived lineage
  • down-regulation is mediated by HIF1A, through recruitment of the HIF1A-inducible transcriptional repressor differentially expressed in chondrocytes protein 1 (DEC1)
  • is involved in various steps of melanoma progression, and GLI2, is a direct transcriptional target of the TGFB1/SMAD pathway and contributes to melanoma progression, exerting antagonistic activities against M-MITF to control melanoma cell invasiveness (PMID: 22496449)
  • 10 initiation site 4815 58 520 retinal pigment epithelium, melanocytes 2007 17438132
  • also called MITF-A or variant 1/isoform 1
  • exon 1A
  • 10 initiation site 4671 56.3 504 heart, cervical cancer, melanocytes, cardiomyocytes 2007 17438132
  • also called MITF-H or variant 2/isoform 2
  • exon 1H
  • expressed by mast cells (Tshori 2007)
  • regulating expression of myosin light-chain 1a (MYL4)(transactivation of MYL4 by Mitf-H in cardiomyocytes is decreased by overexpression of the splice form with exon 6a)(Tshori 2007)
  • 9 initiation site 4286 40.2 357 retinal pigment epithelium, many cell types, melanocytes 2007 17438132
  • also called MITF-Mdel or variant 6/isoform 6
  • exon 1B
  • - - 4685 - 468 - 2006 16337607
    also called variant 7/isoform 7
    10 - 4680 58 519 - 2007 17438132
  • also called MITF-C or variant 3/isoform 3
  • a distinct N-terminus
  • - splicing 1108 10.2 91 - 2007 17438132
  • also called variant 8/isoform 8
  • alternative splicing of a novel 5'-exon onto the common body of the gene and is predicted to encode a unique 43-amino acid sequence at its amino terminus
  • heterodimerizes with a closely related transcription factor, TFE3, and dominantly inhibits the ability of TFE3 to transactivate a melanocyte-specific promoter
  • expressed by mast cells (Tshori 2007)
  • 9 - 4454 46.2 413 - 2007 17438132
    also called variant 5/isoform 5
    Type widely
       expressed in (based on citations)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart   highly
    Digestiveesophagus   highly
    Skin/Tegumentskin   highly
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Connectiveadipose  highly
    Epithelialbarrier liningretinal pigment epithelium (RPE)  
    SystemCellPubmedSpeciesStageRna symbol
    cell lineage
    cell lines
    at STAGE
  • DNA binding protein with basic helix-loop-helix (bHLH), leucine zipper domains
  • a consensus binding sequence for PAX3 homeo domain in the promoter region
  • mono polymer homomer , dimer
    interspecies homolog to murine microphthalmia (mi) transcription factor
    intraspecies paralog to TFEC
  • basic helix loop helix (BHLH) family
  • CATEGORY transcription factor
    SUBCELLULAR LOCALIZATION     intracellular
    basic FUNCTION
  • involved in cell cycle regulation and to play important functions in self-renewal and maintenance of melanocyte stem cells
  • regulator of melanocytes specific expression of the tyrosinase and tyrosinase-related proteins (TYRP1, PEDH) through specific E-box elements (transcription factor for tyrosinase and...)
  • involved in melanogenesis
  • plays a fundamental role in melanocyte development and maintenance and seems to be crucial for the survival of malignant melanocytes
  • may modulate the production of prostaglandin D(2) by activating the PTGDS gene in melanocytes
  • stimulating the transcriptional activity of the proximal region of the Rab27A promoter
  • regulator of cell-type specific functions in melanocytic cells
  • required downstream of oncogenic BRAF because it regulates expression of key cell cycle regulatory proteins such as CDK2 and CDK4
  • activates the expression of melanocyte-specific markers and promotes the survival of embryonic, adult and malignant melanocytes
  • with MEF2A function cooperatively with NFATC1 to transactivate the ATP6V0D2 promoter during RANKL-induced osteoclastogenesis
  • necessary for regulating genes involved in osteoclast differentiation
  • can resides upstream in the transcriptional regulation of DICER1 expression during differentiation of primary human melanocytes
  • occupies and may directly regulate the endogenous DICER1 promoter
  • MITF and CDKN1B are the key molecular switches that control the transition between melanoma-initiating cells and their differentiated progeny
  • promotes melanoma cell proliferation, whereas sustained supression of MITF expression leads to senescence
  • directly regulates a set of genes required for DNA replication, repair and mitosis
  • melanoma-predisposition gene
  • positively regulates skeletal muscle formation; Mitf is significantly expressed during myogenesis, and is required for efficient myotube formation through expression of CDKN1A and ITGA9
  • plays major roles in the development and physiology of vertebrate melanocytes and melanoma cells
  • in conjunction with MITF/TFEC, PAX6 acts as an anti-retinogenic factor, whereas in conjunction with retinogenic genes it acts as a pro-retinogenic factor
  • master regulator of melanocyte development and an important oncogene in melanoma
  • essential role of SWI/SNF for the expression of MITF-dependent and MITF-independent prosurvival factors in melanoma cells
  • acts to promote the development of the retinal pigment epithelium (RPE)
  • potential role for MITF in regulating processes such as optic-fissure closure and bone development or homeostasis
  • important roles for MITF in ocular morphogenesis and bone homeostasis
  • CELLULAR PROCESS nucleotide, transcription, regulation
    signaling sensory transduction/hearing
    a component
    DNA binding to two E-boxes in the proximal region of the Rab27A promoter
    small molecule
  • TBX2 not involved in melanogenesis
  • target of the phosphatidylinositol-3-kinase pathway
  • key transcription factor for PKC-beta (protein kinase C-beta), required to phosphorylate otherwise inactive tyrosinase
  • TFE3 and TFEC proteins may collaborate with MITF to efficiently regulate expression of target genes in osteoclasts
  • MITF regulation of the cathepsin K, CLCN7, and OSTM1 genes, which are critical for osteoclast resorption, suggesting that MITF may be a master regulator of osteoclast function and bone resorption
  • MITF regulation in osteoclasts by PSMD14
  • can interact directly with beta-catenin, the key mediator of the canonical Wnt signaling pathway
  • interaction with 14-3-3 and the kinase MARK3 regulating its movement
  • binds and activates a conserved regulatory element upstream of DICER1 transcriptional start site upon melanocyte differentiation
  • interacting with ATF2 (importance of transcriptionally active ATF2 in melanoma development through fine-tuning of MITF expression)
  • HDAC7 represses MITF at least in part by deacetylation-independent mechanism
  • interacting with USP13 (through deubiquitination, USP13 stabilizes and upregulates MITF protein levels)
  • transcriptional suppression of the MITF gene by DEC1, a HIF1A target that is recruited to the MITF locus under hypoxia
  • HINT1 suppresses specific gene transcription by interacting with the transcription factor MITF in mast cells
  • YY1 cooperates with MITF in regulating the expression of piebaldism gene KIT and multiple additional pigmentation genes
  • in conjunction with MITF/TFEC, PAX6 acts as an anti-retinogenic factor, whereas in conjunction with retinogenic genes it acts as a pro-retinogenic factor
  • PPARGC1A, PPARGC1B coactivators regulate MITF and the tanning response
  • target of BRAF, the melanocyte lineage factor MITF, directly regulates the expression of PPARGC1A
  • BMP4 induces MITF expression in pluripotent stem cells and EDN3 subsequently promotes differentiation of these MITF expressing cells along the melanocyte lineage
  • MITF is a critical regulator of GPNMB expression in dendritic cells
  • SOX5 has a strong inhibitory effect on MITF expression and seems to have a decisive clinical impact on melanoma during tumor progression
  • DDX3X steers MITF protein levels dictating melanoma metastatic potential and response to targeted therapy
  • ABCB5 is a direct target for MITF and its expression can be induced by CTNNB1, a key activator and co-factor for MITF, and and is associated with melanoma differentiation
  • cell & other
    activated by SOX10 and PAX3
    BRAF (BRAF up-regulates MITF transcription through ERK and the transcription factor POU3F2
    Other phosphorylated at the Ser298 by GSK3B to be functional
    phosphorylated by ERK, and this stimulates its activation, but also targets it for degradation through the ubiquitin-proteosome pathway, coupling MITF degradation to its activation
    corresponding disease(s) WS2A , ADFNS , COMMAD
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --other  
    prognostic marker in intermediate thickness melanoma
    tumoral somatic mutation      
    in melanomas (that over 20p100 of the metastatic melanoma cases had alterations in the MITF pathway)
    tumoral       loss of function
    altered MITF function during melanomagenesis can be achieved by MITF amplification, MITF single base substitutions or by mutation of its regulator SOX10
    tumoral   amplification    
    in a subset of melanomas and is thought to be required for sustained proliferation of malignant melanocytes
    constitutional     --over  
    in bone marrow biopsies from patients with systemic mastocytosis and activating KIT mutations (
    Susceptibility to melanoma and renal cell carcinoma (RCC)
    Variant & Polymorphism other
  • rare oncogenic germline substitution, Mi-E318K, that predisposes to both melanoma and RCC
  • Candidate gene
    Therapy target
    combining antiangiogenic therapies with prolyl-hydroxylase inhibition, which stabilize HIF1A is thus of particular interest, to treat melanoma
  • Mitf -/- : mouse with depigmentation, small eyes
  • mouse Mitf mutants exhibit small eyes, deafness, osteopetrosis, and reduced numbers of natural killer and mast cells, and additionally display pigmentation problems varying from complete loss of the melanocytic lineage to ventral spotting in partial loss-of-function settings