Although mutations in ras represent but one of a multitude of genetic events required for conversion of normal cells to the fully malignant state, aberrant upregulation of Ras function causes multiple aspects of the abnormal biology of cancer cells. We propose studies to achieve two broad goals. First, we will delineate the signaling pathways that mediate oncogenic Ras deregulation of the expression of specific genes. Second, we will assess how the products of these genes contribute to malignant transformation of epithelial cells. Specifically, we will evaluate the aberrant action of genes that deregulate progression through the G1 phase of the cell cycle (cyclin DI, p21, and p27), anchorage-independent growth, tumor angiogenesis (VEGF), invasion, and metastasis (MMP-9). Representational difference analysis has also been applied to identify additional gene targets important for Ras oncogenesis. Our rationale for these studies is shaped by recent revelations that Ras signaling is much more complex than simply activating the Raf/MEK/ERK kinase cascade and that cell type differences exist concerning how Ras causes transformation. Our working hypothesis is that, contrary to the """"""""dogma"""""""" established in NIH 3T3 mouse fibroblast studies, oncogenic Ras transformation of epithelial cells is highly dependent on signaling pathways distinct from the Raf/MEK/ERK pathway. The Raf/MEK/ERK cascade has been targeted for the development of anti-Ras drugs for cancer treatment. Since the majority of ras mutations occur in human cancers derived from epithelial cells, an assessment of the relative contribution of Raf-dependent and Raf-independent pathways to Ras transformation of epithelial cells is of obvious importance. Our studies may refocus future efforts to target other Ras signaling pathways for the development of novel therapeutic agents for cancer treatment.
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