There is now substantial and compelling evidence implicating aberrant Rho GTPase function in malignant cancer cell progression and growth. Like Ras, the Ras-related Rho GTPases function as regulated molecular switches activated by diverse extracellular signals that control actin cytoskeletal organization, gene expression, and G1 cell cycle progression. In light of their critical involvement in key cellular processes of normal cells, it is not surprising that the aberrant activation of Rho family proteins (e.g., Racl, RhoA, and Cdc42) contributes to the uncontrolled proliferation, invasion, and metastatic properties of cancer cells. One important outcome of our previous studies was the demonstrated requirement for Rho GTPase function in the transforming activity of Ras and other oncoproteins, as well as in tumor suppressor function. Thus, in contrast to direct mutational activation of Ras, Rho GTPases are activated indirectly in cancer, by perturbations in oncoprotein or tumor suppressor function. Therefore, an emphasis of our studies has been the delineation of the mechanisms by which Rho GTPases are aberrantly deregulated by oncoproteins or tumor suppressors. In the current proposal, we extend this goal with studies that evaluate the involvement of novel members of the Rho family of GTPases (Rnd3, Wrch-1, and Chp) or their activators (Asef) in oncogenesis by Ras and by other oncoproteins (Wnt and beta-catenin) or tumor suppressors (APC). We propose four specific aims to evaluate (1) the involvement of Rnd3 inactivation of RhoA in Ras transformation, (2) the contribution of Wrch-1 to Wnt transformation, (3) the involvement of Chp in Ras and Wnt transformation, and (4) the role of Asef deregulation of Rac in APC tumor suppressor or beta-catenin function. Additional issues that we will address include the regulation of Rho GTPase activity at the level of gene expression, in addition to regulation by GDP/GTP cycling, as well as the possibility that certain Rho GTPases are important therapeutic targets for farnesyltransferase inhibitors that are currently under evaluation as novel anti-cancer drugs in phase II-III clinical trials. The long-term goals of our studies are to validate Rho GTPases as important targets for anti-cancer drug discovery and to delineate their mechanisms of regulation and signaling to define approaches to block their function.
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