MITF (microphthalmia-associated transcription factor)

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MITF (microphthalmia-associated transcription factor)

Written	2013-04	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)

(Note : for Links provided by Atlas : click)

Identity

Alias (NCBI)	CMM8
	MI
	WS2
	WS2A
	bHLHe32
HGNC (Hugo)	MITF
HGNC Alias symb	MI
	bHLHe32
HGNC Alias name	homolog of mouse microphthalmia
HGNC Previous name	WS2A
	WS2
HGNC Previous name	Waardenburg syndrome, type 2A
	microphthalmia-associated transcription factor
	melanogenesis associated transcription factor
LocusID (NCBI)	4286
Atlas_Id	44193
Location	3p14.1 [Link to chromosome band 3p14]
Location_base_pair	Starts at 69936592 and ends at 69968332 bp from pter ( according to GRCh38/hg38-Dec_2013) [Mapping MITF.png]
Local_order	The MITF gene is located between the genes PDHB (telomeric) and PROK2 (centromeric).

Fusion genes
(updated 2017)

Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)

	ACTG1 (17q25.3) / MITF (3p13)	CGGBP1 (3p11.1) / MITF (3p13)	MITF (3p13) / MTERF3 (8q22.1)

Note

Total size: 228903 bps.
MITF has 18 transcripts and encodes a transcription factor that contains both a helix-loop-helix structure as well as a leucine zipper.
Target genes: MITF has been shown to recognize the E-box (CAYRTG) and M-box (TCAYRTG or CAYRTGA) sequences in the promoter regions of multiple target genes, including ACP5, BCL2, BEST1, BIRC7, CDK2, CLCN7, DCT, EDNRB, GPNMB, GPR143, MC1R, MLANA, OSTM1, RAB27A, SILV, SLC45A2, TBX2, TRPM1, TYR and TYRP1 (Hoek et al., 2008b).

DNA/RNA

Description

The gene encompasses 229 kb, and has 9 exons.

Transcription

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).

Description	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.
Expression	Found in most human tissues. Particularly high quantities in retina, uterus, pineal gland, and adipocytes (biogps.org).
Localisation	Nucleus.
Function	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).
Homology	High homology to TFE genes (TFE3, TFEB, TFEC, etc.) and the myc family of bHLH transcription factors (Dickson et al., 2011).

Note	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).
Germinal	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).

Note

Entity	Melanoma
Note	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. There have been linkage and genome wide association studies (GWAS) studies that have shown no evidence to implicate MITF in melanoma (Gillanders et al., 2003; Bishop et al., 2009). However, MITF has been shown to be mutated in a subset of melanomas and overexpressed in others (Garraway et al., 2005; Cronin et al., 2009). This raises the possibility of MITF's involved despite the lack of prior evidence for germline risk. Indeed, individuals with a specific MITF mutation (E318K) have a 5-fold increase risk of developing melanoma (Yokoyama et al., 2011). 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. 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). 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	Renal cell carcinoma
Note	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	Waardenburg syndrome
Note	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 Hirchsprung's syndrome, associated with mutations in 3 genes: SOX10, endothelin 3, and endothelin receptor B (Tassabehji et al., 1995; Widlund and Fisher, 2003).


Entity	Tietz syndrome
Note	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).

	Nomenclature
HGNC (Hugo)	MITF 7105
LRG (Locus Reference Genomic)	LRG_776
	Cards
Atlas	MITFID44193ch3p13
Entrez_Gene (NCBI)	MITF melanocyte inducing transcription factor
Aliases	CMM8; COMMAD; MI; WS2;
	WS2A; bHLHe32
GeneCards (Weizmann)	MITF
Ensembl hg19 (Hinxton)	ENSG00000187098 [Gene_View]
Ensembl hg38 (Hinxton)	ENSG00000187098 [Gene_View] ENSG00000187098 [Sequence] chr3:69936592-69968332 [Contig_View] MITF [Vega]
ICGC DataPortal	ENSG00000187098
TCGA cBioPortal	MITF
AceView (NCBI)	MITF
Genatlas (Paris)	MITF
SOURCE (Princeton)	MITF
Genetics Home Reference (NIH)	MITF
	Genomic and cartography
GoldenPath hg38 (UCSC)	MITF - chr3:69936592-69968332 + 3p13 [Description] (hg38-Dec_2013)
GoldenPath hg19 (UCSC)	MITF - 3p13 [Description] (hg19-Feb_2009)
GoldenPath	MITF - 3p13 [CytoView hg19] MITF - 3p13 [CytoView hg38]
ImmunoBase	ENSG00000187098
genome Data Viewer NCBI	MITF [Mapview hg19]
OMIM	103470 103500 156845 193510 614456 617306
	Gene and transcription
Genbank (Entrez)	AB006909 AB006988 AB006989 AB061771 AK291318
RefSeq transcript (Entrez)	NM_000248 NM_001184967 NM_001184968 NM_001354604 NM_001354605 NM_001354606 NM_001354607 NM_001354608 NM_006722 NM_198158 NM_198159 NM_198177 NM_198178
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)	MITF
Alternative Splicing Gallery	ENSG00000187098
Gene Expression	MITF [ NCBI-GEO ] MITF [ EBI - ARRAY_EXPRESS ] MITF [ SEEK ] MITF [ MEM ]
Gene Expression Viewer (FireBrowse)	MITF [ Firebrowse - Broad ]
Genevisible	Expression of MITF in : [tissues] [cell-lines] [cancer] [perturbations]
BioGPS (Tissue expression)	4286
GTEX Portal (Tissue expression)	MITF
Human Protein Atlas	ENSG00000187098-MITF [pathology] [cell] [tissue]
	Protein : pattern, domain, 3D structure
UniProt/SwissProt	O75030 [function] [subcellular_location] [family_and_domains] [pathology_and_biotech] [ptm_processing] [expression] [interaction]
NextProt	O75030 [Sequence] [Exons] [Medical] [Publications]
With graphics : InterPro	O75030
Splice isoforms : SwissVar	O75030
PhosPhoSitePlus	O75030
Domaine pattern : Prosite (Expaxy)	BHLH (PS50888)
Domains : Interpro (EBI)	bHLH_dom HLH_DNA-bd_sf MiT/TFE_C MiT/TFE_N MITF
Domain families : Pfam (Sanger)	DUF3371 (PF11851) HLH (PF00010) MITF_TFEB_C_3_N (PF15951)
Domain families : Pfam (NCBI)	pfam11851 pfam00010 pfam15951
Domain families : Smart (EMBL)	HLH (SM00353)
Conserved Domain (NCBI)	MITF
Blocks (Seattle)	MITF
PDB (RSDB)	4C7N
PDB Europe	4C7N
PDB (PDBSum)	4C7N
PDB (IMB)	4C7N
Structural Biology KnowledgeBase	4C7N
SCOP (Structural Classification of Proteins)	4C7N
CATH (Classification of proteins structures)	4C7N
Superfamily	O75030
Human Protein Atlas [tissue]	ENSG00000187098-MITF [tissue]
Peptide Atlas	O75030
HPRD	01138
IPI	IPI00023896 IPI00215772 IPI00217203 IPI00217204 IPI00217206 IPI00217209 IPI00217210 IPI00217211 IPI00217212 IPI00293035 IPI00952616 IPI00852788 IPI00944926 IPI01009311 IPI00853423 IPI00985403
	Protein Interaction databases
DIP (DOE-UCLA)	O75030
IntAct (EBI)	O75030
BioGRID	MITF
STRING (EMBL)	MITF
ZODIAC	MITF
	Ontologies - Pathways
QuickGO	O75030
Ontology : AmiGO	negative regulation of transcription by RNA polymerase II nuclear chromatin RNA polymerase II proximal promoter sequence-specific DNA binding DNA-binding transcription factor activity, RNA polymerase II-specific DNA-binding transcription factor activity, RNA polymerase II-specific DNA-binding transcription repressor activity, RNA polymerase II-specific DNA-binding transcription activator activity, RNA polymerase II-specific DNA-binding transcription activator activity, RNA polymerase II-specific chromatin binding protein binding nucleus nucleus nucleoplasm transcription, DNA-templated regulation of transcription, DNA-templated regulation of transcription, DNA-templated positive regulation of gene expression positive regulation of gene expression osteoclast differentiation melanocyte differentiation melanocyte differentiation negative regulation of cell migration protein-containing complex regulation of cell proliferation camera-type eye development canonical Wnt signaling pathway involved in negative regulation of apoptotic process cell fate commitment regulation of osteoclast differentiation positive regulation of transcription, DNA-templated positive regulation of transcription, DNA-templated positive regulation of transcription by RNA polymerase II positive regulation of transcription by RNA polymerase II bone remodeling protein dimerization activity protein-containing complex assembly E-box binding positive regulation of DNA-templated transcription, initiation regulation of RNA biosynthetic process
Ontology : EGO-EBI	negative regulation of transcription by RNA polymerase II nuclear chromatin RNA polymerase II proximal promoter sequence-specific DNA binding DNA-binding transcription factor activity, RNA polymerase II-specific DNA-binding transcription factor activity, RNA polymerase II-specific DNA-binding transcription repressor activity, RNA polymerase II-specific DNA-binding transcription activator activity, RNA polymerase II-specific DNA-binding transcription activator activity, RNA polymerase II-specific chromatin binding protein binding nucleus nucleus nucleoplasm transcription, DNA-templated regulation of transcription, DNA-templated regulation of transcription, DNA-templated positive regulation of gene expression positive regulation of gene expression osteoclast differentiation melanocyte differentiation melanocyte differentiation negative regulation of cell migration protein-containing complex regulation of cell proliferation camera-type eye development canonical Wnt signaling pathway involved in negative regulation of apoptotic process cell fate commitment regulation of osteoclast differentiation positive regulation of transcription, DNA-templated positive regulation of transcription, DNA-templated positive regulation of transcription by RNA polymerase II positive regulation of transcription by RNA polymerase II bone remodeling protein dimerization activity protein-containing complex assembly E-box binding positive regulation of DNA-templated transcription, initiation regulation of RNA biosynthetic process
Pathways : KEGG	Osteoclast differentiation Melanogenesis Pathways in cancer Melanoma
REACTOME	O75030 [protein]
REACTOME Pathways	R-HSA-3232118 [pathway]
NDEx Network	MITF
Atlas of Cancer Signalling Network	MITF
Wikipedia pathways	MITF
	Orthology - Evolution
OrthoDB	4286
GeneTree (enSembl)	ENSG00000187098
Phylogenetic Trees/Animal Genes : TreeFam	MITF
HOGENOM	O75030
Homologs : HomoloGene	MITF
Homology/Alignments : Family Browser (UCSC)	MITF
	Gene fusions - Rearrangements
Fusion : Mitelman	ACTG1/MITF [17q25.3/3p13]
Fusion : Mitelman	CGGBP1/MITF [3p11.1/3p13]
Fusion : Mitelman	MITF/MTERF3 [3p13/8q22.1]
Fusion Portal	CGGBP1 3p11.1 MITF 3p13 HNSC
Fusion Portal	MITF 3p13 MTERFD1 BRCA
Fusion : Fusion_Hub	ACTG1--MITF ATAD2B--MITF ATP11A--MITF CACNA2D3--MITF CADM2--MITF CCAR1--MITF CGGBP1--MITF EIF4E3--MITF FOXP1--MITF FRMD4B--MITF LTBP1--MITF MAGI1--MITF MITF--ACTG1 MITF--C9ORF3 MITF--CEP57
	MITF--COG3 MITF--EIF4G3 MITF--FOXP1 MITF--HSD17B4 MITF--KLC1 MITF--MBP MITF--MCF2L2 MITF--MED13 MITF--MTERF3 MITF--MTERFD1 MITF--MYO1B MITF--NAA35 MITF--PPAP2B MITF--PPP4R2 MITF--PRICKLE2
	MITF--PTDSS1 MITF--RCL1 MITF--RSBN1L MITF--THRB MITF--TMEM167A MITF--VGLL4 PRCC--MITF ROBO1--MITF SGOL2--MITF ZNF292--MITF
Fusion : Quiver	MITF
	Polymorphisms : SNP and Copy number variants
NCBI Variation Viewer	MITF [hg38]
dbVar	MITF
ClinVar	MITF
Monarch	MITF
1000_Genomes	MITF
Exome Variant Server	MITF
GNOMAD Browser	ENSG00000187098
Varsome Browser	MITF
Genomic Variants (DGV)	MITF [DGVbeta]
DECIPHER	MITF [patients] [syndromes] [variants] [genes]
CONAN: Copy Number Analysis	MITF
	Mutations
ICGC Data Portal	MITF
TCGA Data Portal	MITF
Broad Tumor Portal	MITF
OASIS Portal	MITF [ Somatic mutations - Copy number]
Cancer Gene: Census	MITF
Somatic Mutations in Cancer : COSMIC	MITF [overview] [genome browser] [tissue] [distribution]
Somatic Mutations in Cancer : COSMIC3D	MITF
Mutations and Diseases : HGMD	MITF
LOVD (Leiden Open Variation Database)	Whole genome datasets
LOVD (Leiden Open Variation Database)	LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)	LOVD 3.0 shared installation
LOVD (Leiden Open Variation Database)	MSeqDR-LSDB Mitochondrial Disease Locus Specific Database
LOVD (Leiden Open Variation Database)	LOVD - Leiden Open Variation Database
BioMuta	search MITF
DgiDB (Drug Gene Interaction Database)	MITF
DoCM (Curated mutations)	MITF (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)	MITF (select a term)
intoGen	MITF
OncoKB	MITF
NCG6 (London)	select MITF
Cancer3D	MITF(select the gene name)
Impact of mutations	[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
	Diseases
OMIM	103470 103500 156845 193510 614456 617306
Orphanet	220 3560 21641 22112 20874 22933 10575
DisGeNET	MITF
Medgen	MITF
Genetic Testing Registry	MITF
NextProt	O75030 [Medical]
GENETests	MITF
Target Validation	MITF
Huge Navigator	MITF [HugePedia]
ClinGen	MITF (curated)
	Clinical trials, drugs, therapy
MyCancerGenome	MITF
Protein Interactions : CTD
Pharm GKB Gene	PA30823
Pharos	O75030
Clinical trial	MITF
	Miscellaneous
canSAR (ICR)	MITF (select the gene name)
Harmonizome	MITF
DataMed Index	MITF
	Probes
	Litterature
PubMed	311 Pubmed reference(s) in Entrez
GeneRIFs	Gene References Into Functions (Entrez)
EVEX	MITF

REVIEW articles	automatic search in PubMed
Last year publications	automatic search in PubMed