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| Malignant melanoma is the deadliest form of skin cancer.It arises from epidermal melanocytes, the pigment producing cells in the skin, or their progenitors. Currently, melanoma metastasis is only preventable by early detection and surgical excision of primary tumors; hence, there is an immediate need to understand the mechanisms underlying melanocyte transformation. We utilize cDNA expression and RNA interference approaches to alter key signaling pathway in primary human melanocytes and a panel of melanoma cells characterizing different stages of melanoma progression. In order to closely mimic the in vivo environment, we test the role of target proteins in a 3-D skin reconstruct model. The serine-threonine kinase, B-RAF, is mutated in 50-70% of melanomas and integrin receptors that bind fibronectin are frequently up-regulated. We are investigating the role of B-RAF in promoting proliferation, invasion and resistance to apoptosis in human melanoma cells. We have shown that mutant B-RAF regulates melanoma cell proliferation through uncontrolled activation of ERK1/2, controls the Cks1/Skp2 ubiquitin ligase that targets p27Kip1 for proteasomal degradation. However, our recent studies show that Skp2 regulates melanoma cell cycle progression in a manner independent of p27Kip1 but dependent on p53. The depth of melanoma invasion is a clinical determinant of poor prognosis. We are also investigating the role of Rnd3, an antagonist of RhoA-ROCK signaling, that is required for melanoma cell invasion and migration in 3-D.Mutant B-RAF regulates the expression of Rnd3 and Rnd3 regulates the actin cytoskeleton, focal adhesions and melanoma cell invasion. Melanoma is renowned for its resistance to cell death.B-RAF coordinately with fibronectin signaling regulates melanoma cell survival. We are elucidating the underlying mechanisms by examining the regulation and role of Bcl-2 family proteins. Finally, we are investigating the role of stromal cells in melanoma progression. Ultimately, we expect to identify the mechanisms underlying invasive growth of melanomas and, in doing so, identify novel targets for therapeutic intervention. Keywords: melanoma, metastasis , B-RAF, stromal cells | ||||
| Selected Publications Boisvert-Adamo K, Longmate W, Abel EV, Aplin, AE. Mcl-1 is required for melanoma resistance to anoikis. Mol Cancer Res, 2009. In press. Klein RM, Aplin AE. Rnd3 regulation of the actin cytoskeleton promotes melanoma migration and invasive outgrowth in three dimensions. Cancer Res. 69: 1-8, 2009. Hu R, Aplin AE. Skp2 regulates G2/M progression in a p53-dependent manner. Mol Biol Cell. 19(11):4602-10, 2008. ( Abstract ) Boisvert-Adamo K, Aplin AE. Mutant B-RAF mediates resistance to anoikis via Bad and Bim. Oncogene. 27(23):3301-12, 2008. ( Abstract ) Klein RM, Spofford LS, Abel EV, Ortiz A, Aplin AE. B-RAF regulation of Rnd3 participates in actin cytoskeletal and focal adhesion organization. Mol Biol Cell. 19(2):498-508, 2008. ( Abstract ) Chen C, Seth AK, Aplin AE. Genetic and expression aberrations of E3 ubiquitin ligases in human breast cancer. Mol Cancer Res. 4(10):695-707, 2006. ( Abstract ) Bhatt KV, Hu R, Spofford LS, Aplin AE. Mutant B-RAF signaling and cyclin D1 regulate Cks1/S-phase kinase-associated protein 2-mediated degradation of p27Kip1 in human melanoma cells. Oncogene. 26(7):1056-66, 2007. ( Abstract ) Spofford LS, Abel EV, Boisvert-Adamo K, Aplin AE. Cyclin D3 expression in melanoma cells is regulated by adhesion-dependent phosphatidylinositol 3-kinase signaling and contributes to G1-S progression. J Biol Chem. 281(35):25644-51, 2006. ( Abstract ) Boisvert-Adamo K, Aplin AE. B-RAF and PI-3 kinase signaling protect melanoma cells from anoikis. Oncogene. 25(35):4848-56, 2006. ( Abstract ) Bhatt KV, Spofford LS, Aram G, McMullen M, Pumiglia K, Aplin AE. Adhesion control of cyclin D1 and p27Kip1 levels is deregulated in melanoma cells through BRAF-MEK-ERK signaling. Oncogene. 24(21):3459-71, 2005. ( Abstract ) | ||||
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