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Gene Section
Review
MITF (microphthalmia-associated transcription
factor)
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)
Published in Atlas Database: April 2013
Online updated version : http://AtlasGeneticsOncology.org/Genes/MITFID44193ch3p13.html
DOI: 10.4267/2042/51811
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2013 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Exon 1 is variable and the domains within it are the
transactivation domain (TAD) and the beta-helix-loophelix-zipper (B-HLH-Zip).
Some isoforms are specific for certain cells types, i.e.
M: melanocytes, MC: mast cells (Levy et al., 2006).
Identity
Other names: CMM8, MI, WS2, WS2A, bHLHe32
Location: 3p14.1
Local order: The MITF gene is located between the
genes PDHB (telomeric) and PROK2 (centromeric).
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).
Protein
Description
The gene encompasses 229 kb, and has 9 exons.
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.
Transcription
Expression
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.
Found in most human tissues.
Particularly high quantities in retina, uterus, pineal
gland, and adipocytes (biogps.org).
DNA/RNA
Description
Localisation
Nucleus.
Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11)
735
MITF (microphthalmia-associated transcription factor)
Riddle ND, Zhang P
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).
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, MART1), 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 melanomainhibitor-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).
Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11)
Homology
High homology to TFE genes (TFE3, TFEB, TFEC,
etc.) and the myc family of bHLH transcription factors
(Dickson et al., 2011).
Mutations
Note
The MITF promoter is partially regulated by certain
transcription factors such as PAX3, SOX10, LEF1/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).
736
MITF (microphthalmia-associated transcription factor)
Riddle ND, Zhang P
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.
Implicated in
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 upregulation 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).
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 (KleinWaardenburg 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).
Renal cell carcinoma
Note
Malignant transformation of the renal parenchyma.
Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11)
737
MITF (microphthalmia-associated transcription factor)
Riddle ND, Zhang P
Granter SR, Weilbaecher KN, Quigley C, Fisher DE. Role for
microphthalmia transcription factor in the diagnosis of
metastatic malignant melanoma. Appl Immunohistochem Mol
Morphol. 2002 Mar;10(1):47-51
Tietz syndrome
Note
An autosomal dominant disorder characterized by
generalized hypopigmentation (fair skin and lightcolored 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).
McGill GG, Horstmann M, Widlund HR, Du J et al.. Bcl2
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Fisher DE. MLANA/MART1 and SILV/PMEL17/GP100 are
transcriptionally regulated by MITF in melanocytes and
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Gillanders E, Juo SH, Holland EA, Jones M et al.. Localization
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Widlund HR, Fisher DE. Microphthalamia-associated
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2003
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Du J, Widlund HR, Horstmann MA, Ramaswamy S, Ross K,
Huber WE, Nishimura EK, Golub TR, Fisher DE. Critical role of
CDK2 for melanoma growth linked to its melanocyte-specific
transcriptional regulation by MITF. Cancer Cell. 2004
Dec;6(6):565-76
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