Our group studies cell death/proliferation signals in relation to development and disease, particularly cancer. We attempt to understand critical modes of cell homeostasis with a goal of molecular targeted therapy for human disease.
1) p53, Apoptosis, and Cancer Therapy . p53 mutations are the most common genetic aberrancy in human cancer and confer tumor cell resistance to apoptosis by many drugs. We study apoptosis in p53 wild type or deficient tumor cells containing defined oncogenes. In addition we have constructed a cell-free apoptosis assay which recapitulates p53's regulatory role, allowing for molecular dissection and direct biochemical purification of death mediators. These studies have identified key intermediates and several negative modulators of p53-dependent apoptosis which may be targets for cancer drug design.
2) Control of life and death in melanoma . Malignant transformation of melanocytes produces one of the most treatment resistant malignancies in man. We have identified a transcriptional network which regulates melanoma cell survival and proliferation as well as melanocyte differentiation during development. Using diverse methods including mouse models, human tumor expression arrays, and cellular assays, we examine mechanisms through which melanoma cells evade death, with the goal of improving therapy. These studies also include examination of the role of UV in melanocyte biology and carcinogenesis.
3) MITF transcription factor family in development & cancer . Mitf is a helix-loop-helix factor homologous to Myc, whose mutation produces absence of melanocytes and severe abnormalities in osteoclasts, the cells responsible for bone mineral resorption. Mitf mutations occur in humans with the pigmentation/deafness condition Waardenburg Syndrome. Mitf acts as a master regulator of melanocyte and osteoclast development and is targeted by several critical signaling pathways. Recently, members of the Mitf family have been discovered as oncogenes in a variety of human malignancies. Their roles in cancer as well as means of targeting them for therapeutic benefit are under active investigation.
Hemesath, T.J, Price, ER, Takemoto, C, Badalian, T, and Fisher, DE. MAPK links the transcription factor Mitf to c-Kit signaling in melanocytes. Nature 391:298-301 (1998)
McGill GC, Horstmann M, Widlund HR, Du J, Motyckova G, Nishimura EK, Lin YL, Ramaswamy S, Avery W, Ding HF, Jordan SA, Jackson IJ, Korsmeyer SJ, Golub TR, Fisher DE. Bcl2 regulation by the melanocyte master regulator Mitf modulates lineage survival and melanoma cell viability. Cell . 2002 Jun 14;109(6):707-18.
Davis IJ, Hsi BL, Arroyo JD, Vargas SO, Yeh YA, Motyckova G, Valencia P, Perez- Atayde AR, Argani P, Ladanyi M, Fletcher JA, Fisher DE. Cloning of an Alpha-TFEB fusion in renal tumors harboring the t(6;11)(p21;q13) chromosome translocation. Proc Natl Acad Sci U S A 2003 May 13;100(10):6051-6056