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FLASH GENE

Symbol

MITF

contributors: mct - updated : 03-09-2017

HGNC name	microphthalmia-associated transcription factor
HGNC id	7105

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

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

DNA

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

RNA

TRANSCRIPTS	type	messenger

text	at least nine promoters driving expression of alternative first exons (PMID: 21949374)

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_000248 9 - 4472 NP_000239 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) NM_198159 10 initiation site 4815 NP_937802 58 520 retinal pigment epithelium, melanocytes 2007 17438132 also called MITF-A or variant 1/isoform 1 exon 1A NM_198177 10 initiation site 4671 NP_937820 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) NM_198178 9 initiation site 4286 NP_937821 40.2 357 retinal pigment epithelium, many cell types, melanocytes 2007 17438132 also called MITF-Mdel or variant 6/isoform 6 exon 1B NM_001184967 - - 4685 NP_001171896 - 468 - 2006 16337607 also called variant 7/isoform 7 NM_006722 10 - 4680 NP_006713 58 519 - 2007 17438132 also called MITF-C or variant 3/isoform 3 a distinct N-terminus NM_001184968 - splicing 1108 NP_001171897 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) NM_198158 9 - 4454 NP_937801 46.2 413 - 2007 17438132 also called variant 5/isoform 5

EXPRESSION

Type

widely

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Cardiovascular heart       highly Digestive esophagus       highly Skin/Tegument skin       highly Visual eye retina

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Connective adipose     highly Epithelial barrier lining retinal pigment epithelium (RPE)

cells

System Cell Pubmed Species Stage Rna symbol Skeleton osteoclast Skin/Tegument melanocyte

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	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

HOMOLOGY

interspecies

homolog to murine microphthalmia (mi) transcription factor

intraspecies

paralog to TFEC

Homologene

FAMILY

basic helix loop helix (BHLH) family

CATEGORY

transcription factor

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,nucleus

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

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

sensory transduction/hearing

a component

INTERACTION

DNA	binding to two E-boxes in the proximal region of the Rab27A promoter

RNA

small molecule

protein	TYR, TYRP1, DCT
	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

REGULATION

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

ASSOCIATED DISORDERS

corresponding disease(s)

WS2A , ADFNS , COMMAD

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein 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
Marker
Therapy target
	System Type Disorder Pubmed cancer skin   combining antiangiogenic therapies with prolyl-hydroxylase inhibition, which stabilize HIF1A is thus of particular interest, to treat melanoma

ANIMAL & CELL MODELS

	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