Ras deregulation of rho gtpase function which are

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Unformatted text preview: ho GTPase function, which are important regulators of cell-cell and cell-substrate contacts, may also cause significant changes in cellular adhesion (23). Oncogenic RAS stimulates the expression of several proteases that break down the extracellular matrix including urokinase plasminogen activator (uPA), its receptor (uPAR) and matrix metalloproteases (MMP-2 and MMP-9) (94). Optimal stimulation of uPA and MMP-9 gene expression by RAS requires signaling through MAPK and JNK responsive promoter elements(95). Local degradation of the extracellular matrix by these enzymes promotes tumor angiogenesis. Therefore, theses enzymes have critical role in the control of both tumor cell migration and tumor angiogenesis. RAS oncogenes stimulate the production of growth factors involved in angiogenesis including VEGF and bFGF. Since oncogenic RAS promotes VEGF expression, tumor harboring mutant RAS often express high levels of VEGF, one of the most potent angiogenesis stimulating growth factors. Inhibition of mutant KRAS gene expression 22 in human colon cancer cells, either through expression of a ribozyme or through antisense oligonucleotides, inhibited the expression of VEGF. In addition, tumorderived cell lines transfected with an activated HRAS gene showed increased expression of VEGF-A (95). Furthermore, inhibition of RAS signaling (either by dominant negative RAS or by farnesyltransferase inhibitors (FTIs) prevents efficient hypoxia-induced VEGF mRNA synthesis and protein secretion in malignant human astrocytoma cells that do not harbor RAS mutations. Thus, the induction of VEGF synthesis by hypoxia requires activation of the RAS pathway (95). Oncogenic RAS reduces the production of anti-angiogenic factors including thrombospondin-1 and thrombospondin-2. It has been shown that whereas tumor cells expressing activated RAS show elevated levels of VEGF, the levels of thrombospondin-1 and thrombospondin-2 are dramatically reduced. These two extracellular matrix glycoproteins are negative regulators of angiogenesis. Repression of thrombos...
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