Ras and Rho regulation of the cell cycle and oncogenesis

The important contribution of aberrant Ras activation in oncogenesis is well established. Our knowledge of the signaling pathways that are regulated by Ras is considerable. However, the number of downstream effectors of Ras continues to increase and our understanding of the role of these effector signaling pathways in mediating oncogenesis is far from complete and continues to evolve. Similarly, our understanding of the components that control mitogen-stimulated cell cycle progression is also very advanced. Where our understanding has lagged has been the delineation of the mechanism by which Ras causes a deregulation of cell cycle progression to promote the uncontrolled proliferation of the cancer cell. In this review, we summarize our current knowledge of how deregulated Ras activation alters the function of cyclin D1, p21 Cip1, and p27 Kip1. The two themes that we have emphasized are the involvement of Rho small GTPases in cell cycle regulation and the cell-type differences in how Ras signaling interfaces with the cell cycle machinery.