Microphthalmia (Mi) is a Myc-related transcription factor essential for melanocyte development. Mi deficiency in humans with Waardenburg Syndrome 2A or mice produces melanocyte absence. In the current grant period we have extensively characterized Mi's DNA binding specificity that may coordinately regulate the 3 major pigment enzyme gene promoters. We found that Mi expression is profoundly regulated by Melanocyte Stimulating Hormone (MSH) via a cAMP signaling cascade whose effects on Mi's promoter are melanocyte-specific. These findings suggest that Mi participates in the differentiation pathway for pigmentation. However, Mi is also essential for melanocyte viability. Along these lines we have identified Mi as a target of c-Kit signaling in melanocytes, and elucidated a pathway in which Kit superactivates Mi via phosphorylation, recruitment of a transcriptional coactivator, and regulation of Mi stability. We also found that Mi expression is regulated by Wnt signaling via b-catenin that is aberrantly upregulated or mutated in a significant fraction of human melanomas. Mi may regulate S phase entry and mediate the mitogenic effect of b-catenin. The current proposal builds on these pigmentation and proliferation roles for Mi. The First Specific Aim will mechanistically examine Mi's biochemical modification by phosphorylations that alter transactivation potential and stability. The Second Specific Aim will focus on how the Mi promoter is regulated in a tissue-restricted fashion in melanocytes. Pathways impinging on this promoter include MSH and Wnt signaling. Promoter analyses will be done in vitro and in vivo validated using transgenic mice. The Third Specific Aim will dissect Mi's cell cycle regulatory activity both mechanistically in vitro and using mouse models that address Mi's role in melanoma proliferation. The final Specific Aim is a large effort to identify Mi's transcriptional target genes. We have initiated pilot studies together with researchers at the MIT Genome Center using oligonucleotide arrays, and will examine Mi's targets in primary melanocytes, in the context of signaling pathways that utilize Mi (MSH and c-Kit). Through an understanding of the means by which Mi is regulated as well as the transcriptional program(s) it activates, Mi may reveal a great deal about melanocyte biology.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR043369-07
Application #
6475561
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Moshell, Alan N
Project Start
1996-02-20
Project End
2005-11-30
Budget Start
2002-03-01
Budget End
2003-02-28
Support Year
7
Fiscal Year
2002
Total Cost
$332,120
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:
Byrne, Elizabeth H; Fisher, David E (2017) Immune and molecular correlates in melanoma treated with immune checkpoint blockade. Cancer 123:2143-2153
Lin, William M; Fisher, David E (2017) Signaling and Immune Regulation in Melanoma Development and Responses to Therapy. Annu Rev Pathol 12:75-102
Kawakami, Akinori; Fisher, David E (2017) The master role of microphthalmia-associated transcription factor in melanocyte and melanoma biology. Lab Invest 97:649-656
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

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