Malignant melanoma is a deadly malignancy due to its high propensity to metastatize and its resistance to existing therapies. There are currently no treatments that increase life expectancy once metastatic disease presents. Molecular analyses of familial and sporadic melanomas have identified a number of oncogenic alterations including Ras, B-Raf, PTEN, Akt, and Ink4a/Arf. Though Ras driven pathways have been studied for a number of years, we have observed significant differences in downstream effectors of Ras and in the complex biological functions that result under different physiologic contexts. Using a transgenic mouse with targeted expression of Ras in melanocytes we have experimentally validated the importance of expression of an activated Ras and downstream signaling pathways in melanoma development and tumor progression. The microenvironment of the tumor, in particular hypoxia, has been shown to act as a selective pressure effecting tumor progression and therapeutic resistance. We have found that the skin possess reduced oxygen tension that could both enhance the malignant potential of melanocytes with an activated Ras oncogene or Akt gene and may contribute to melanocyte survival, by passing senescence. Constitutive activation of Akt3, has been described in melanoma progression. Akt activation, both Ras-dependent and independent, leads to anti-apoptotic signaling as well as dysregulation of cap dependent translation. Using transgenic mice that we developed (Akt3 and Ras) and knock out mice (PTEN, VHL, HIF1a) and melanocytes cultured from these mice, we propose to identify the mechanism by which activation of the PI3kinse-Akt-mTOR pathway in the presence of a hypoxic microenvironment (or activated HIF1a) support melanocyte survival and promote melanocyte transformation. We will substantiate our observation in the mouse systems with studies of human melanocytic lesions and cultured human melanocytes and melanoma cells under similar conditions. Identification of the essential genetic elements in Akt pathway and the impact of the microenvironment of the skin on melanocyte survival and transformation provide crucial information for the development of effective therapeutic and chemopreventive agents. ? ? ?
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