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MITF  -  microphthalmia-associated transcription...

Homo sapiens

Synonyms: BHLHE32, CMM8, Class E basic helix-loop-helix protein 32, MI, Microphthalmia-associated transcription factor, ...
 
 
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Disease relevance of MITF

 

High impact information on MITF

  • We further show that PAX3 proteins associated with WS1 in either the paired domain or the homeodomain fail to recognize and transactivate the MITF promoter [3].
  • We have previously shown that MITF transactivates the gene for tyrosinase, a key enzyme for melanogenesis, and is critically involved in melanocyte differentiation [3].
  • Epistatic relationship between Waardenburg syndrome genes MITF and PAX3 [3].
  • Most cloned cells of MITF transfectants exhibited dendritic morphology and expressed melanogenic markers, but such properties were not observed in cells transfected with closely related TFE3 cDNA [2].
  • Our findings indicate that MITF is critically involved in melanocyte differentiation [2].
 

Chemical compound and disease context of MITF

  • Expression levels of MITF and CDK2 are tightly correlated in primary melanoma specimens and predict susceptibility to the CDK2 inhibitor roscovitine [7].
  • In the present report, using recombinant adenovirus encoding the wild-type or a dominant negative form of MITF, as well as stable cell lines expressing tetracycline inducible wild-type MITF, we reassessed the role of MITF in melanocyte differentiation and in the regulation of melanin synthesis [8].
  • We studied a series of 11 cellular neurothekeomas using paraffin immunoperoxidase staining with microphthalmia transcription factor (Mitf), NKI/C3, and S-100 [9].
 

Biological context of MITF

 

Anatomical context of MITF

  • Here we show that ectopic expression of MITF converts NIH/3T3 fibroblasts into cells with characteristics of melanocytes [2].
  • In addition, MITF and TRPM1 mRNA levels were correlated tightly across a series of human melanoma cell lines [12].
  • For this purpose, the effect of co-expression of cDNA encoding MITF on MC1R promoter activity in NIH/3T3 cells was studied [13].
  • Microphthalmia-associated transcription factor (MITF) regulates the differentiation and development of melanocytes and retinal pigment epithelium and is also responsible for pigment cell-specific transcription of the melanogenesis enzyme genes [14].
  • Co-transfection of an expression vector for MITF-M, the MITF isoform specific for pigment cells, or empty control vector with a full-length PKC-beta promoter-CAT (chloramphenicol acetyltransferase) reporter construct (PKC-beta/CAT) into Cos-7 cells showed >60-fold increase in CAT activity [15].
 

Associations of MITF with chemical compounds

 

Physical interactions of MITF

 

Enzymatic interactions of MITF

  • Using this antibody, we could demonstrate that MITF was rapidly and persistently phosphorylated upon stimulation of primary osteoclasts with RANKL and that phosphorylation of Ser(307) correlated with expression of the target gene tartrate-resistant acid phosphatase [24].
 

Regulatory relationships of MITF

  • In this report, the possibility was examined that MITF might additionally regulate expression of the SILV and MLANA genes [25].
  • This prompted examination of whether MITF also might transcriptionally regulate TRPM1 expression [12].
  • These data suggest that protein factors that modulate the activity of MITF in melanoma cells repress TYRP1 and presumably other MITF target genes [26].
  • Promoter deletion and mutational analyses indicate that SOX10 can activate MITF expression through binding to a region that is evolutionarily conserved between the mouse and human MITF promoters [27].
  • Here we show that Mitf can redirect beta-catenin transcriptional activity away from canonical Wnt signaling-regulated genes toward Mitf-specific target promoters to activate transcription [28].
  • Gene expression profiling has been used to identify large numbers of target genes [29].
  • High throughput sequencing has also been used to identify many new target genes [30].
 

Other interactions of MITF

  • Here we show that PAX3, a transcription factor with a paired domain and a homeodomain, transactivates the MITF promoter [3].
  • This study therefore suggests that the MITF/TFE3 family is a new class of nuclear modulators for LEF-1, which may ensure efficient propagation of Wnt signals in many types of cells [10].
  • Interaction among SOX10, PAX3 and MITF, three genes altered in Waardenburg syndrome [4].
  • Based on these results we conclude that the RCC-associated t(6;11)(p21;q13) translocation leads to a dramatic transcriptional and translational upregulation of TFEB due to promoter substitution, thereby severely unbalancing the nuclear ratios of the MITF/TFE subfamily members [31].
  • The promoter activation caused by MITF is dependent on each CATGTG motif of the distal enhancer element, the M box, and the initiator E box of the tyrosinase gene and the TRP-1 M box [32].
 

Analytical, diagnostic and therapeutic context of MITF

  • The TRPM1 promoter contains multiple MITF consensus binding elements that were seen by chromatin immunoprecipitation to be occupied by endogenous MITF within melanoma cells [12].
  • MITF knockdown by small interfering RNA (siRNA) in cell culture revealed a strong correlation between MITF and VMD2 mRNA levels [33].
  • Analysis using in vivo electroporation with constructs containing mutation of each E-box indicated that expression in native RPE requires both E-boxes, yet in vitro DNA binding studies suggested that MITF binds well to E-box 1 but only minimally to E-box 2 [33].
  • The authors tested 15 AMLs with T311 and D5 by immunohistochemistry and a subset of 3 cases by reverse transcription-polymerase chain reaction for their expression of tyrosinase and Mitf mRNA [34].
  • The transcription activation domain of microphthalmia transcription factor, tested as a GAL-MITF fusion protein, remained fully functional in these cells, however, and ectopic microphthalmia transcription factor localized normally to the nucleus and bound to the tyrosinase initiator E-box in gel retardation assays [35].

References

  1. Bcl2 regulation by the melanocyte master regulator Mitf modulates lineage survival and melanoma cell viability. McGill, G.G., Horstmann, M., Widlund, H.R., Du, J., Motyckova, G., Nishimura, E.K., Lin, Y.L., Ramaswamy, S., Avery, W., Ding, H.F., Jordan, S.A., Jackson, I.J., Korsmeyer, S.J., Golub, T.R., Fisher, D.E. Cell (2002) [Pubmed]
  2. Ectopic expression of MITF, a gene for Waardenburg syndrome type 2, converts fibroblasts to cells with melanocyte characteristics. Tachibana, M., Takeda, K., Nobukuni, Y., Urabe, K., Long, J.E., Meyers, K.A., Aaronson, S.A., Miki, T. Nat. Genet. (1996) [Pubmed]
  3. Epistatic relationship between Waardenburg syndrome genes MITF and PAX3. Watanabe, A., Takeda, K., Ploplis, B., Tachibana, M. Nat. Genet. (1998) [Pubmed]
  4. Interaction among SOX10, PAX3 and MITF, three genes altered in Waardenburg syndrome. Bondurand, N., Pingault, V., Goerich, D.E., Lemort, N., Sock, E., Caignec, C.L., Wegner, M., Goossens, M. Hum. Mol. Genet. (2000) [Pubmed]
  5. Molecular bases of congenital hypopigmentary disorders in humans and oculocutaneous albinism 1 in Japan. Tomita, Y., Miyamura, Y., Kono, M., Nakamura, R., Matsunaga, J. Pigment Cell Res. (2000) [Pubmed]
  6. Microphthalmia-associated transcription factor gene amplification in metastatic melanoma is a prognostic marker for patient survival, but not a predictive marker for chemosensitivity and chemotherapy response. Ugurel, S., Houben, R., Schrama, D., Voigt, H., Zapatka, M., Schadendorf, D., Bröcker, E.B., Becker, J.C. Clin. Cancer Res. (2007) [Pubmed]
  7. Critical role of CDK2 for melanoma growth linked to its melanocyte-specific transcriptional regulation by MITF. Du, J., Widlund, H.R., Horstmann, M.A., Ramaswamy, S., Ross, K., Huber, W.E., Nishimura, E.K., Golub, T.R., Fisher, D.E. Cancer Cell (2004) [Pubmed]
  8. Microphthalmia-associated transcription factor (MITF) is required but is not sufficient to induce the expression of melanogenic genes. Gaggioli, C., Buscà, R., Abbe, P., Ortonne, J.P., Ballotti, R. Pigment Cell Res. (2003) [Pubmed]
  9. Microphthalmia transcription factor and NKI/C3 expression in cellular neurothekeoma. Page, R.N., King, R., Mihm, M.C., Googe, P.B. Mod. Pathol. (2004) [Pubmed]
  10. Microphthalmia-associated transcription factor interacts with LEF-1, a mediator of Wnt signaling. Yasumoto, K., Takeda, K., Saito, H., Watanabe, K., Takahashi, K., Shibahara, S. EMBO J. (2002) [Pubmed]
  11. Sox10 and Pax3 physically interact to mediate activation of a conserved c-RET enhancer. Lang, D., Epstein, J.A. Hum. Mol. Genet. (2003) [Pubmed]
  12. Transcriptional regulation of the melanoma prognostic marker melastatin (TRPM1) by MITF in melanocytes and melanoma. Miller, A.J., Du, J., Rowan, S., Hershey, C.L., Widlund, H.R., Fisher, D.E. Cancer Res. (2004) [Pubmed]
  13. Involvement of microphthalmia-associated transcription factor (MITF) in expression of human melanocortin-1 receptor (MC1R). Aoki, H., Moro, O. Life Sci. (2002) [Pubmed]
  14. Microphthalmia-associated transcription factor (MITF): multiplicity in structure, function, and regulation. Shibahara, S., Takeda, K., Yasumoto, K., Udono, T., Watanabe, K., Saito, H., Takahashi, K. J. Investig. Dermatol. Symp. Proc. (2001) [Pubmed]
  15. MITF mediates cAMP-induced protein kinase C-beta expression in human melanocytes. Park, H.Y., Wu, C., Yonemoto, L., Murphy-Smith, M., Wu, H., Stachur, C.M., Gilchrest, B.A. Biochem. J. (2006) [Pubmed]
  16. Melanocytes and the microphthalmia transcription factor network. Steingrímsson, E., Copeland, N.G., Jenkins, N.A. Annu. Rev. Genet. (2004) [Pubmed]
  17. Regulation of microphthalmia-associated transcription factor MITF protein levels by association with the ubiquitin-conjugating enzyme hUBC9. Xu, W., Gong, L., Haddad, M.M., Bischof, O., Campisi, J., Yeh, E.T., Medrano, E.E. Exp. Cell Res. (2000) [Pubmed]
  18. Differential regulation of melanosomal proteins after hinokitiol treatment. Choi, Y.G., Bae, E.J., Kim, D.S., Park, S.H., Kwon, S.B., Na, J.I., Park, K.C. J. Dermatol. Sci. (2006) [Pubmed]
  19. Ser298 of MITF, a mutation site in Waardenburg syndrome type 2, is a phosphorylation site with functional significance. Takeda, K., Takemoto, C., Kobayashi, I., Watanabe, A., Nobukuni, Y., Fisher, D.E., Tachibana, M. Hum. Mol. Genet. (2000) [Pubmed]
  20. Sumoylation of MITF and its related family members TFE3 and TFEB. Miller, A.J., Levy, C., Davis, I.J., Razin, E., Fisher, D.E. J. Biol. Chem. (2005) [Pubmed]
  21. Evidence to suggest that expression of MITF induces melanocyte differentiation and haploinsufficiency of MITF causes Waardenburg syndrome type 2A. Tachibana, M. Pigment Cell Res. (1997) [Pubmed]
  22. Analysis of the VMD2 promoter and implication of E-box binding factors in its regulation. Esumi, N., Oshima, Y., Li, Y., Campochiaro, P.A., Zack, D.J. J. Biol. Chem. (2004) [Pubmed]
  23. Genetics of pigment cells: lessons from the tyrosinase gene family. Murisier, F., Beermann, F. Histol. Histopathol. (2006) [Pubmed]
  24. Microphthalmia transcription factor is a target of the p38 MAPK pathway in response to receptor activator of NF-kappa B ligand signaling. Mansky, K.C., Sankar, U., Han, J., Ostrowski, M.C. J. Biol. Chem. (2002) [Pubmed]
  25. MLANA/MART1 and SILV/PMEL17/GP100 are transcriptionally regulated by MITF in melanocytes and melanoma. Du, J., Miller, A.J., Widlund, H.R., Horstmann, M.A., Ramaswamy, S., Fisher, D.E. Am. J. Pathol. (2003) [Pubmed]
  26. Selective down-regulation of tyrosinase family gene TYRP1 by inhibition of the activity of melanocyte transcription factor, MITF. Fang, D., Tsuji, Y., Setaluri, V. Nucleic Acids Res. (2002) [Pubmed]
  27. Transcription factor hierarchy in Waardenburg syndrome: regulation of MITF expression by SOX10 and PAX3. Potterf, S.B., Furumura, M., Dunn, K.J., Arnheiter, H., Pavan, W.J. Hum. Genet. (2000) [Pubmed]
  28. The Microphthalmia-Associated Transcription Factor Mitf Interacts with {beta}-Catenin To Determine Target Gene Expression. Schepsky, A., Bruser, K., Gunnarsson, G.J., Goodall, J., Hallsson, J.H., Goding, C.R., Steingrimsson, E., Hecht, A. Mol. Cell. Biol. (2006) [Pubmed]
  29. Novel MITF targets identified using a two-step DNA microarray strategy. Hoek, K.S., Schlegel, N.C., Eichhoff, O.M., Widmer, D.S., Praetorius, C., Einarsson, S.O., Valgeirsdottir, S., Bergsteinsdottir, K., Schepsky, A., Dummer, R., Steingrimsson, E. Pigment. Cell. Melanoma. Res. (2008) [Pubmed]
  30. Essential role of microphthalmia transcription factor for DNA replication, mitosis and genomic stability in melanoma. Strub, T., Giuliano, S., Ye, T., Bonet, C., Keime, C., Kobi, D., Le Gras, S., Cormont, M., Ballotti, R., Bertolotto, C., Davidson, I. Oncogene. (2011) [Pubmed]
  31. Upregulation of the transcription factor TFEB in t(6;11)(p21;q13)-positive renal cell carcinomas due to promoter substitution. Kuiper, R.P., Schepens, M., Thijssen, J., van Asseldonk, M., van den Berg, E., Bridge, J., Schuuring, E., Schoenmakers, E.F., van Kessel, A.G. Hum. Mol. Genet. (2003) [Pubmed]
  32. Functional analysis of microphthalmia-associated transcription factor in pigment cell-specific transcription of the human tyrosinase family genes. Yasumoto, K., Yokoyama, K., Takahashi, K., Tomita, Y., Shibahara, S. J. Biol. Chem. (1997) [Pubmed]
  33. VMD2 promoter requires two proximal E-box sites for its activity in vivo and is regulated by the MITF-TFE family. Esumi, N., Kachi, S., Campochiaro, P.A., Zack, D.J. J. Biol. Chem. (2007) [Pubmed]
  34. Immunohistochemical and reverse transcription-polymerase chain reaction expression analysis of tyrosinase and microphthalmia-associated transcription factor in angiomyolipomas. Jungbluth, A.A., King, R., Fisher, D.E., Iversen, K., Coplan, K., Kolb, D., Williamson, B., Chen, Y.T., Stockert, E., Old, L.J., Busam, K.J. Appl. Immunohistochem. Mol. Morphol. (2001) [Pubmed]
  35. Transcriptional repression of the microphthalmia gene in melanoma cells correlates with the unresponsiveness of target genes to ectopic microphthalmia-associated transcription factor. Vachtenheim, J., Novotna, H., Ghanem, G. J. Invest. Dermatol. (2001) [Pubmed]
 
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