Microphthalmia-associated transcription factor

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Microphthalmia-associated transcription factor
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols MITF ; CMM8; MI; WS2; WS2A; bHLHe32
External IDs OMIM156845 MGI104554 HomoloGene4892 ChEMBL: 1741165 GeneCards: MITF Gene
RNA expression pattern
PBB GE MITF 207233 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 4286 17342
Ensembl ENSG00000187098 ENSMUSG00000035158
UniProt O75030 Q08874
RefSeq (mRNA) NM_000248 NM_001113198
RefSeq (protein) NP_000239 NP_001106669
Location (UCSC) Chr 3:
69.79 – 70.02 Mb
Chr 6:
97.81 – 98.02 Mb
PubMed search [1] [2]

Microphthalmia-associated transcription factor (MITF) is a basic helix-loop-helix leucine zipper transcription factor involved in melanocyte[1] and osteoclast development.[2] MITF is the most characterized member of the MIT family. Its gene resides at the mi locus in mice,[3] and mutation of this gene results in deafness, bone loss, small eyes, and poorly pigmented eyes and skin.[4] The primary cell types affected in MITF-deficient mice are mast cells, osteoclasts, and melanocytes[4]

Clinical significance[edit]

Clinical genetics[edit]

Germline mutations of MITF are associated with Tietz syndrome[5] and Waardenburg syndrome type IIa.[6]

Role in Cancer[edit]

One study found that MITF is repressed by SUMOylation through the discovery of an activating germline mutation in the MITF gene that inhibits SUMOylation in the context of melanoma and renal cell carcinoma.[7]

Target genes[edit]

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,

ACP5[8][9] BCL2[9][10] BEST1[9][11] BIRC7[9][12]
CDK2[9][13] CLCN7[9][14] DCT[9][15] EDNRB[9][16]
GPNMB[9][17] GPR143[9][18] MC1R[9][19] MLANA[9][20]
OSTM1[9][14] RAB27A[9][21] SILV[9][20] SLC45A2[9][22]
TBX2[9][23] TRPM1[9][24] TYR[9][25] TYRP1[9][26]

Additional genes identified by a microarray study (which confirmed the above targets) include the following,[9]

MBP TNFRSF14 IRF4 RBM35A
PLA1A APOLD1 KCNN2 INPP4B
CAPN3 LGALS3 GREB1 FRMD4B
SLC1A4 TBC1D16 GMPR ASAH1
MICAL1 TMC6 ITPKB SLC7A8

Interactions[edit]

MITF has been shown to interact with PATZ1,[27] PIAS3,[28] TFE3,[29][30] UBE2I,[31] HINT1,[32] and LEF1.[15]

The LysRS-Ap4A-MITF signaling pathway[edit]

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.[33] 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.[34] 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.[35][36]

See also[edit]

References[edit]

  1. ^ Levy C, Khaled M, Fisher DE (2006). "MITF: master regulator of melanocyte development and melanoma oncogene". Trends Mol Med 12 (9): 406–14. doi:10.1016/j.molmed.2006.07.008. PMID 16899407. 
  2. ^ 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. 
  3. ^ 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)
  4. ^ a b Moore, K. J. Insight into the microphthalmia gene. Trends Genet 11, 442-448 (1995).
  5. ^ Smith SD, Kelley PM, Kenyon JB, Hoover D (2000). "Tietz syndrome (hypopigmentation/deafness) caused by mutation of MITF". J. Med. Genet. 37 (6): 446–8. doi:10.1136/jmg.37.6.446. PMC 1734605. PMID 10851256. 
  6. ^ Tachibana M, Kobayashi Y, Matsushima Y (2003). "Mouse models for four types of Waardenburg syndrome". Pigment Cell Res. 16 (5): 448–54. doi:10.1034/j.1600-0749.2003.00066.x. PMID 12950719. 
  7. ^ Bertolotto C, Lesueur F, Giuliano S, Strub T, de Lichy M, Bille K, Dessen P, d'Hayer B, Mohamdi H, et al. (2011). "A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma". Nature 480 (7375): 94–8. doi:10.1038/nature10539. PMID 22012259. 
  8. ^ 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. 
  9. ^ a b c d e f g h i j k l m n o p q r s t u 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. 
  10. ^ 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. 
  11. ^ 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. 
  12. ^ 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. 
  13. ^ 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. 
  14. ^ a b 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. 
  15. ^ a b 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. 
  16. ^ 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. 
  17. ^ 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. 
  18. ^ 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. 
  19. ^ 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. 
  20. ^ a b 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. 
  21. ^ 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. 
  22. ^ 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. 
  23. ^ 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. 
  24. ^ 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. 
  25. ^ 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. 
  26. ^ 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. 
  27. ^ 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. 
  28. ^ 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. 
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  30. ^ 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. 
  31. ^ 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. 
  32. ^ 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. 
  33. ^ 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. 
  34. ^ 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. 
  35. ^ 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. 
  36. ^ 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. 

External links[edit]