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
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)
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
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
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
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
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
