Mutations in the Microphthalmia (Mi) gene represent one of the oldest recognized causes of melanocyte death in mice (manifest as coat color abnormalities). Mi mutations have recently also been shown to occur in humans with the pigmentation disorder Waardenburg Syndrome Type 2. Mi is a factor whose function is clearly critical to melanocyte development. The Mi gene was recently cloned and encodes a factor with substantial homology to the Myc oncoprotein in a basic/helix-loop-helix/leucine zipper (b-HLH-ZlP) domain. Mi is one of the only proteins in this family which displays tissue specific expression. We have defined the DNA specificity of Mi and found it to bind and potently activate transcription off a promoter element previously shown to confer melanocyte specific expression of pigmentation genes. The conservation of this """"""""M box"""""""" element in a number of melanocyte specific gene promoters, Mi's ability to activate it, and the devastating effects of Mi mutations on melanocyte survival strongly suggest that Mi is a master regulator for pigmentation and melanocyte development. We have also found three other b-HLH-ZIP factors with which Mi will heterodimerize (TFEB, TFEC, and TFE3) collectively called the """"""""MiT"""""""" family. Despite its restricted expression, we have found Mi mRNA in all 13 melanomas examined to date, suggesting that like Myc its expression may modulate proliferation. We also found that the chromosomal map site for one of its dimerization partners (TFEB) is also frequently amplified in melanoma. Our characterization of 7 mutant alleles of Mi (each derived from a different mouse strain) revealed clustered mutations in or near the DNA binding domain. We found striking correlations between their inherited phenotypic severity and their biochemical behavior through structure/function studies. To further enhance our understanding of this factor and extend our analysis of its actions in melanocytes and melanoma, this grant proposes to : 1) examine Mi's protein:protein and protein: DNA recognition properties, 2) determine the transcriptional activities of Mi as well as its 3 binding partners we have identified, 3) analyze Mi expression using 51 protection, RT-PCR, and antibody directed protein analyses in melanocytes, and melanomas, 4) transfect wild type Mi and mutant which we have characterized into a variety of cells to study Mi's roles in melanocyte differentiated and proliferation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR043369-02
Application #
2006443
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1996-02-20
Project End
2000-11-30
Budget Start
1996-12-01
Budget End
1997-11-30
Support Year
2
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02215
Nguyen, Nhu T; Fisher, David E (2018) MITF and UV responses in skin: From pigmentation to addiction. Pigment Cell Melanoma Res :
Kapp, Friedrich G; Perlin, Julie R; Hagedorn, Elliott J et al. (2018) Protection from UV light is an evolutionarily conserved feature of the haematopoietic niche. Nature 558:445-448
Hejna, Miroslav; Moon, Wooyoung M; Cheng, Jeffrey et al. (2018) Local genomic features predict the distinct and overlapping binding patterns of the bHLH-Zip family oncoproteins MITF and MYC-MAX. Pigment Cell Melanoma Res :
Wein, Marc N; Foretz, Marc; Fisher, David E et al. (2018) Salt-Inducible Kinases: Physiology, Regulation by cAMP, and Therapeutic Potential. Trends Endocrinol Metab 29:723-735
Levy, Carmit; Golan, Tamar; Fisher, David E (2018) miRNA-211 stops the clock. Noncoding RNA Investig 2:
Song, J S; London, W B; Hawryluk, E B et al. (2017) Risk of melanocytic nevi and nonmelanoma skin cancer in children after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 52:989-997
Alves, Cleidson P; Yokoyama, Satoru; Goedert, Lucas et al. (2017) MYO5A Gene Is a Target of MITF in Melanocytes. J Invest Dermatol 137:985-989
Salma, Nunciada; Song, Jun S; Kawakami, Akinori et al. (2017) Tfe3 and Tfeb Transcriptionally Regulate Peroxisome Proliferator-Activated Receptor ?2 Expression in Adipocytes and Mediate Adiponectin and Glucose Levels in Mice. Mol Cell Biol 37:
Chen, Xiqun; Chen, Hongxiang; Cai, Waijiao et al. (2017) The melanoma-linked ""redhead"" MC1R influences dopaminergic neuron survival. Ann Neurol 81:395-406
Mujahid, Nisma; Liang, Yanke; Murakami, Ryo et al. (2017) A UV-Independent Topical Small-Molecule Approach for Melanin Production in Human Skin. Cell Rep 19:2177-2184

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