Microphthalmia-associated transcription factor
|Microphthalmia-associated transcription factor|
|Symbols||; CMM8; MI; WS2; WS2A; bHLHe32|
|External IDs||ChEMBL: GeneCards:|
|RNA expression pattern|
Microphthalmia-associated transcription factor (MITF) is a basic helix-loop-helix leucine zipper transcription factor involved in lineage-specific pathway regulation of many types of cells including melanocytes, osteoclasts, and mast cells.  The term “lineage specific,” as it relates to MITF, means genes or traits that are only found in a certain cell type. Therefore, MITF may be involved in the rewiring of signaling cascades that are specifically required for the survival and physiological function of their normal cell precursors. 
MITF is the most characterized member of the MIT family. Its gene resides at the mi locus in mice, and its protumorogenic targets include factors involved in cell death, DNA replication, repair, mitosis, microRNA production, membrane trafficking, mitochondrial metabolism, and much more.  Mutation of this gene results in deafness, bone loss, small eyes, and poorly pigmented eyes and skin. MITF is the most characterized member of the MIT family. In human subjects, because it is known that MITF controls the expression of various genes that are essential for normal melanin synthesis in melanocytes, mutations of MITF can lead to diseases such as Melanoma, Waardenburg syndrome, and Tietz syndrome. 
An understanding of MITF is necessary to understand how certain lineage-specific cancers and other diseases progress. In addition, current and future research can lead to potential avenues to target this transcription factor mechanism for cancer prevention.
Implications of MITF Mutation
Waardenburg syndrome is a rare genetic disorder. It’s symptoms include deafness, minor defects, and abnormalities in pigmentation.  Mutations in the MITF gene have been found in certain patients with Waardenburg syndrome, type II. Mutations that change the amino acid sequence of that result in an abnormally small MITF are found. These mutations disrupt dimer formation, and as a result cause insufficient development of melanocytes. The shortage of melanocytes causes some of the characteristic features of Waardenburg syndrome. 
Tietz syndrome, first described in 1923, is a congenital disorder often characterized by deafness and leucism. Tietz is caused by a mutation in the MITF gene.  The mutation in MITF deletes or changes a single amino acid base pair specifically in the base motif region of the MITF protein. The new MITF protein is unable to bind to DNA and melanocyte development and subsequently melanin production is altered. A reduced number of melanocytes can lead to hearing loss, and decreased melanin production can account for the light skin and hair color that make Tietz syndrome so noticeable. 
MITF and Melanoma
Melanocytes are commonly known as cells that are responsible for producing the pigment melanin which gives coloration to the hair, skin, and nails. The exact mechanisms of how exactly melanocytes become cancerous are relatively unclear, but there is ongoing research to gain more information about the process. For example, it has been uncovered that the DNA of certain genes is often damaged in melanoma cells, most likely as a result of damage from UV radiation, and in turn increases the likelihood of developing melanoma.  Specifically, it has been found that a large percentage of melanomas have mutations in the B-RAF gene which leads to melanoma by causing an MEK-ERK kinase cascade when activated.  In addition to B-RAF, MITF is also known to play a crucial role in melanoma progression. Since it is a transcription factor that is involved in the regulation of genes related to invasiveness, migration, and metastasis, it can play a role in the progression of melanoma. Figure 1 shows the specific activators and targets of MITF that are related to the the survival, migration, proliferation, invasion and metastasis of melanoma cells.
MITF recognizes E-box (CAYRTG) and M-box (TCAYRTG or CAYRTGA) sequences in the promoter regions of target genes. Known target genes (confirmed by at least two independent sources) of this transcription factor include,
Additional genes identified by a microarray study (which confirmed the above targets) include the following,
Most transcription factors function in cooperation with other factors by protein-protein interactions. Association of MITF with other proteins is a critical step in the regulation of MITF-mediated transcriptional activity. Some commonly studied MITF interactions include those with MAZR, PIAS3, Tfe3, hUBC9, PKC1, and LEF1. Looking at the variety of structures gives insight into MITF's varied roles in the cell.
The Myc-associated zinc-finger protein related factor (MAZR) interacts with the Zip domain of MITF. When expressed together, both MAZR and MITF increase promoter activity of the mMCP-6 gene. MAZR and MITF together transactivate the mMCP-6 gene. MAZR also plays a role in the phenotypic expression of mast cells in association with MITF. 
PIAS3 is a transcriptional inhibiter that acts by inhibiting STAT3's DNA binding activity. PIAS3 directly interacts with MITF, and STAT3 does not interfere with the interaction between PIAS3 and MITF. PIAS3 functions as a key molecule in suppressing the transcriptional activity of MITF. This is important when considering mast cell and melanocyte development. 
MITF and TFE3 are both part of the basic helix-loop-helix-leucine zipper family of transcription factors. Each protein encoded by the family of transcription factors can bind DNA. MITF is necessary for melanocyte and eye development, and new research suggests that TFE3 is also required for osteoclast development, a function redundant of MITF. The combined loss of both genes results in severe osteopetrosis, pointing to an interaction between MITF and other members of its transcription factor family. 
UBC9 is a ubiquitin conjugating enzyme whose proteins associates with MITF. Although hUBC9 is known to act preferentially with SENTRIN/SUMO1, an in vitro analysis demonstrated greater actual association with MITF. hUBC9 is a critical regulator of melanocyte differentiation. To do this, it targets MITF for proteasome degradation.
Protein kinase C-interacting protein 1 (PKC1) associates with MITF. Their association is reduced upon cell activation. When this happens MITF disengages from PKC1. PKC1 by itself, found in the cytosol and nucleus, has no known physiological function. It does, however, have the ability to suppress MITF transcriptional activity and can function as an in vivo negative regulator of MITF induced transcriptional activity. 
The functional cooperation between MITF and the lymphoid enhancing factor (LEF-1) results in a synergistic transactivation of the dopachrome tautomerase gene promoter, which is an early melanoblast marker. LEF-1 is involved in the process of regulation by Wnt signaling. LEF-1 also cooperates with MITF-related proteins like TFE3. MITF is a modulator of LEF-1, and this regulation ensures efficient propagation of Wnt signals in many cells..
The LysRS-Ap4A-MITF signaling pathway
The LysRS-Ap4A-MITF signaling pathway was first discovered in mast cells, in which, the MAPK pathway is activated upon allergen stimulation. Lysyl-tRNA synthetase (LysRS), which normally resides in the multisynthetase complex with other tRNA sythetases, is phosphorylated on Serine 207 in a MAPK-dependent manner. This phosphorylation causes LysRS to change its conformation, detach from the complex and translocate into the nucleus, where it associates with the MITF-HINT1 inhibitory complex. The conformational change switches LysRS activity from aminoacylation of Lysine tRNA to diadenosine tetraphosphate (Ap4A) production. Ap4A binds to HINT1, which releases MITF from the inhibitory complex, allowing it to transcribe its target genes. Activation of the LysRS-Ap4A-MITF signaling pathway by isoproterenol has been confirmed in cardiomyocytes, where MITF is a major regulator of cardiac growth and hypertrophy.
- Hershey CL, Fisher DE (2004). "MITF and TFE3: members of a b-HLH-ZIP transcription factor family essential for osteoclast development and function". Bone 34 (4): 689–96. doi:10.1016/j.bone.2003.08.014. PMID 15050900.
- Garraway, L.A.; Sellers, W.R. (2006). "Lineage dependency and lineage survival oncogenes in human cancer". Nat. Rev. Cancer 6: 593–602.
- Hughes, M. J., J.B., L., Krakowsky, J. M. & Anderson, K. P. A helix-loop-helix transcription factor-like gene is located at the mi locus. J. Biol. Chem. 268, 20687-20690 (1993)
- Cheli, Y.; Ohanna, M.; Ballotti, R.; Bertolotto, C. (2010). "Fifteen-year quest for microphthalmia-associated transcription factor target genes". Pigment Cell Melanoma Res 23: 27–40.
- Moore, K. J. (1995). "Insight into the microphthalmia gene". Trends Genet' 11: 442–448.
- "Genetics Home Reference". National Institutes of Health.
- Kumar, Sudesh, and Kiran Rao. “Waardenburg Syndrome: A Rare Genetic Disorder, A Report of Two Cases.” Indian Journal of Human Genetics 18.2 (2012): 254-255. Academic Search Premier. Web. 4 Apr. 2014.,
- Vachtenheim, J; Ondrusova, L (2013). "A Critical Transcription Factor in Melanoma Transcriptional Regulatory Network". Recent Advances in the Biology, Therapy and Management of Melanoma 4: 71-73.
- Smith SD, Kelley PM, Kenyon JB, Hoover D (Jun 2000). "Tietz syndrome (hypopigmentation/deafness) caused by mutation of MITF" (Free full text). J. Med. Genet. 37 (6): 446–448. doi:10.1136/jmg.37.6.446. PMC 1734605. PMID 10851256.
- “Melanoma Skin Cancer. “ American Cancer Society, 29. Oct. 2014. Web. 15 Oct. 2014. <http://www.cancer.org/acs/groups/cid/documents/webcontent/003120-pdf.pdf>
- Luchin A, Purdom G, Murphy K, et al. (2000). "The microphthalmia transcription factor reulates expression of the tartrate-resistant acid phosphatase gene during terminal differentiation of osteoclasts". J. Bone Miner. Res. 15 (3): 451–460. doi:10.1359/jbmr.2000.15.3.451. PMID 10750559.
- Hoek KS, Schlegel NC, Eichhoff OM, et al. (2008). "Novel MITF targets identified using a two-step DNA microarray strategy". Pigment Cell Melanoma Res. 21 (6): 665–76. doi:10.1111/j.1755-148X.2008.00505.x. PMID 19067971.
- McGill GG, Horstmann M, Widlund HR, et al. (2002). "BCL2 regulation by the melanocyte master regulator MITF modulates lineage survival and melanoma cell viability". Cell 109 (6): 707–18. doi:10.1016/S0092-8674(02)00762-6. PMID 12086670.
- Esumi N, Kachi S, Campochiaro PA, et al. (2007). "VMD2 promoter requires two proximal E-box sites for its activity in vivo and is regulated by the MITF-TFE family". J. Biol. Chem. 282 (3): 1838–50. doi:10.1074/jbc.M609517200. PMID 17085443.
- Dynek JN, Chan SM, Liu J, et al. (2008). "Microphthalmia-associated transcription factor is a critical transcriptional regulator of melanoma inhibitor of apoptosis in melanomas". Cancer Res. 68 (9): 3124–32. doi:10.1158/0008-5472.CAN-07-6622. PMID 18451137.
- Du J, Widlund HR, Horstmann MA, et al. (2004). "Critical role of CDK2 for melanoma growth linked to its melanocyte-specific transcriptional regulation by MITF". Cancer Cell 6 (6): 565–76. doi:10.1016/j.ccr.2004.10.014. PMID 15607961.
- Meadows NA, Sharma SM, Faulkner GJ, et al. (2007). "The expression of Clcn7 and Ostm1 in osteoclasts is coregulated by microphthalmia transcription factor". J. Biol. Chem. 282 (3): 1891–904. doi:10.1074/jbc.M608572200. PMID 17105730.
- Yasumoto K, Takeda K, Saito H, et al. (2002). "Microphthalmia-associated transcription factor interacts with LEF-1, a mediator of Wnt signaling". EMBO J. 21 (11): 2703–14. doi:10.1093/emboj/21.11.2703. PMC 126018. PMID 12032083.
- Sato-Jin K, Nishimura EK, Akasaka E, et al. (2008). "Epistatic connections between microphthalmia-associated transcription factor and endothelin signaling in Waardenburg syndrome and other pigmentary disorders". FASEB J. 22 (4): 1155–68. doi:10.1096/fj.07-9080com. PMID 18039926.
- Loftus SK, Antonellis A, Matera I, et al. (2009). "Gpnmb is a Melanoblast-Expressed, MITF-Dependent Gene". Pigment Cell Melanoma Res. 22 (1): 99–110. doi:10.1111/j.1755-148X.2008.00518.x. PMC 2714741. PMID 18983539.
- Vetrini F, Auricchio A, Du J, Angeletti B, et al. (2004). "The microphthalmia transcription factor (MITF) controls expression of the ocular albinism type 1 gene: link between melanin synthesis and melanosome biogenesis". Mol. Cell. Biol. 24 (15): 6550–9. doi:10.1128/MCB.24.15.6550-6559.2004. PMC 444869. PMID 15254223.
- Aoki H, Moro O (2002). "Involvement of microphthalmia-associated transcription factor (MITF) in expression of human melanocortin-1 receptor (MC1R)". Life Sci. 71 (18): 2171–9. doi:10.1016/S0024-3205(02)01996-3. PMID 12204775.
- Du J, Miller AJ, Widlund HR, et al. (2003). "MLANA/MART1 and SILV/PMEL17/GP100 are transcriptionally regulated by MITF in melanocytes and melanoma". Am. J. Pathol. 163 (1): 333–43. doi:10.1016/S0002-9440(10)63657-7. PMC 1868174. PMID 12819038.
- Chiaverini C, Beuret L, Flori E, et al. (2008). "Microphthalmia-associated transcription factor regulates RAB27A gene expression and controls melanosome transport". J. Biol. Chem. 283 (18): 12635–42. doi:10.1074/jbc.M800130200. PMID 18281284.
- Du J, Fisher DE (2002). "Identification of Aim-1 as the underwhite mouse mutant and its transcriptional regulation by MITF". J. Biol. Chem. 277 (1): 402–6. doi:10.1074/jbc.M110229200. PMID 11700328.
- Carreira S, Liu B, Goding CR (2000). "The gene encoding the T-box factor Tbx2 is a target for the microphthalmia-associated transcription factor in melanocytes". J. Biol. Chem. 275 (29): 21920–7. doi:10.1074/jbc.M000035200. PMID 10770922.
- Miller AJ, Du J, Rowan S, et al. (2004). "Transcriptional regulation of the melanoma prognostic marker melastatin (TRPM1) by MITF in melanocytes and melanoma". Cancer Res. 64 (2): 509–16. doi:10.1158/0008-5472.CAN-03-2440. PMID 14744763.
- Hou L, Panthier JJ, Arnheiter H (2000). "Signaling and transcriptional regulation in the neural crest-derived melanocyte lineage: interactions between KIT and MITF". Development 127 (24): 5379–89. PMID 11076759.
- Fang D, Tsuji Y, Setaluri V (2002). "Selective down-regulation of tyrosinase family gene TYRP1 by inhibition of the activity of melanocyte transcription factor, MITF". Nucleic Acids Res. 30 (14): 3096–106. doi:10.1093/nar/gkf424. PMC 135745. PMID 12136092.
- Morii E, Oboki K, Kataoka TR, Igarashi K, Kitamura Y (March 2002). "Interaction and cooperation of mi transcription factor (MITF) and myc-associated zinc-finger protein-related factor (MAZR) for transcription of mouse mast cell protease 6 gene". J. Biol. Chem. 277 (10): 8566–71. doi:10.1074/jbc.M110392200. PMID 11751862.
- Levy C, Nechushtan H, Razin E (January 2002). "A new role for the STAT3 inhibitor, PIAS3: a repressor of microphthalmia transcription factor". J. Biol. Chem. 277 (3): 1962–6. doi:10.1074/jbc.M109236200. PMID 11709556.
- Steingrimsson E, Tessarollo L, Pathak B, Hou L, Arnheiter H, Copeland NG, Jenkins NA (April 2002). "Mitf and Tfe3, two members of the Mitf-Tfe family of bHLH-Zip transcription factors, have important but functionally redundant roles in osteoclast development". Proc. Natl. Acad. Sci. U.S.A. 99 (7): 4477–82. doi:10.1073/pnas.072071099. PMC 123673. PMID 11930005.
- Mansky KC, Sulzbacher S, Purdom G, Nelsen L, Hume DA, Rehli M, Ostrowski MC (February 2002). "The microphthalmia transcription factor and the related helix-loop-helix zipper factors TFE-3 and TFE-C collaborate to activate the tartrate-resistant acid phosphatase promoter". J. Leukoc. Biol. 71 (2): 304–10. PMID 11818452.
- Xu W, Gong L, Haddad MM, Bischof O, Campisi J, Yeh ET, Medrano EE (March 2000). "Regulation of microphthalmia-associated transcription factor MITF protein levels by association with the ubiquitin-conjugating enzyme hUBC9". Exp. Cell Res. 255 (2): 135–43. doi:10.1006/excr.2000.4803. PMID 10694430.
- Razin E, Zhang ZC, Nechushtan H, Frenkel S, Lee YN, Arudchandran R, Rivera J (November 1999). "Suppression of microphthalmia transcriptional activity by its association with protein kinase C-interacting protein 1 in mast cells". J. Biol. Chem. 274 (48): 34272–6. doi:10.1074/jbc.274.48.34272. PMID 10567402.
- Yannay-Cohen N, Carmi-Levy I, Kay G, Yang CM, Han JM, Kemeny DM, Kim S, Nechushtan H, Razin E (June 2009). "LysRS serves as a key signaling molecule in the immune response by regulating gene expression". Mol Cell 34 (5): 603–11. doi:10.1016/j.molcel.2009.05.019. PMID 19524539.
- Lee YN, Nechushtan H, Figov N, Razin E (February 2004). "The function of lysyl-tRNA synthetase and Ap4A as signaling regulators of MITF activity in FcepsilonRI-activated mast cells". Immunity 20 (2): 145–51. doi:10.1016/S1074-7613(04)00020-2. PMID 14975237.
- Tshori S, Gilon D, Beeri R, Nechushtan H, Kaluzhny D, Pikarsky E, Razin E (October 2006). "Transcription factor MITF regulates cardiac growth and hypertrophy". J. Clin. Invest. 116 (10): 2673–81. doi:10.1172/JCI27643. PMC 1570375. PMID 16998588.
- Carmi-Levy I, Yannay-Cohen N, Kay G, Razin E, Nechushtan H (September 2008). "Diadenosine tetraphosphate hydrolase is part of the transcriptional regulation network in immunologically activated mast cells". Mol. Cell. Biol. 28 (18): 5777–84. doi:10.1128/MCB.00106-08. PMC 2546939. PMID 18644867.
- Microphthalmia-associated transcription factor at the US National Library of Medicine Medical Subject Headings (MeSH)