The long-term goal of this project is to understand how apoptosis influences the development and growth of malignant melanoma (MM). Preliminary studies indicate that survivin, a newly recognized inhibitor of apoptosis, is broadly expressed in human nevi, MM lesions and melanoma cell lines, but not in normal melanocytes. A four-year mentored program is proposed to investigate the hypothesis that expression of survivin is an important early step in the transformation from normal melanocyte to melanoma and represents a potential therapeutic target in MM. This program will incorporate both didactic and research training in three general areas: apoptosis, melanocyte and melanoma biology, and adenoviral-mediated gene transfer. The training will be guided by a mentor (Dario Altieri, M.D.), 2 collaborators (Ruth Halaban, Ph.D., Alfred Bothwell, Ph.D.), and an advisory committee of 5 additional senior scientists with expertise in these areas.
Three specific aims are proposed. First, modulation of survivin expression and function will be studied in cultured human melanocytes in vitro. Melanocytes will be stimulated by UV radiation and growth factors to induce survivin expression, and the effects of (adenoviral-mediated) survivin expression on apoptosis resistance, proliferation, dendricity and melanogenesis will be examined. Second, mechanisms of survivin inhibition of apoptosis in nevi and melanoma cells will be investigated. Nevus cells will be transfected with survivin antisense and a dominant negative survivin point mutant to block survivin function. Melanoma cell lines expressing these antagonists under the control of a tetracycline-regulated promoter will be used to investigate the timing of apoptosis and identify the intracellular target(s) of survivin action. Third, an in vivo model will be developed using these cell lines in SCID mice to study the role of survivin in melanoma tumor development. In addition, survivin antagonists will be directly targeted to tumors using adenoviruses. The proposed studies promise to elucidate the mechanisms of apoptosis regulation in MM, and may identify new molecular approaches for the therapeutic intervention in cancer.
| Raj, Deepak; Brash, Douglas E; Grossman, Douglas (2006) Keratinocyte apoptosis in epidermal development and disease. J Invest Dermatol 126:243-57 |
| Zhang, Wengeng; Hanks, Adrianne N; Boucher, Kenneth et al. (2005) UVB-induced apoptosis drives clonal expansion during skin tumor development. Carcinogenesis 26:249-57 |
| Brash, Douglas E; Zhang, Wengeng; Grossman, Douglas et al. (2005) Colonization of adjacent stem cell compartments by mutant keratinocytes. Semin Cancer Biol 15:97-102 |
| Florell, Scott R; Bowen, Anneli R; Hanks, Adrianne N et al. (2005) Proliferation, apoptosis, and survivin expression in a spectrum of melanocytic nevi. J Cutan Pathol 32:45-9 |
| Liu, Tong; Brouha, Brook; Grossman, Douglas (2004) Rapid induction of mitochondrial events and caspase-independent apoptosis in Survivin-targeted melanoma cells. Oncogene 23:39-48 |
| Bowen, Anneli R; Hanks, Adrianne N; Murphy, Kelley J et al. (2004) Proliferation, apoptosis, and survivin expression in keratinocytic neoplasms and hyperplasias. Am J Dermatopathol 26:177-81 |
| Liu, Jihua; Dai, Qiang; Chen, Jun et al. (2003) Phospholipid scramblase 3 controls mitochondrial structure, function, and apoptotic response. Mol Cancer Res 1:892-902 |
| Florell, Scott R; Schmidt, Soo J; Porter-Gill, Patricia et al. (2003) Novel application of a fibrin cell block method to evaluate melanocytic cell populations. Pigment Cell Res 16:662-9 |
| Allen, Sarah M; Florell, Scott R; Hanks, Adrianne N et al. (2003) Survivin expression in mouse skin prevents papilloma regression and promotes chemical-induced tumor progression. Cancer Res 63:567-72 |
| Bowen, Anneli R; Hanks, Adrianne N; Allen, Sarah M et al. (2003) Apoptosis regulators and responses in human melanocytic and keratinocytic cells. J Invest Dermatol 120:48-55 |
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