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.
Pruitt
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University of North Carolina at Chapel Hill, Lineberger Comprehensive Cancer Center, Department of Pharmacology, Chapel Hill, NC 27599-7295, USA.
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D016475:3T3 Cells / Q000166:cytology / Q000378:metabolism; D000818:Animals; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000378:metabolism / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002471:Cell Transformation, Neoplastic; D019938:Cyclin D1 / Q000235:genetics / Q000502:physiology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000502:physiology; D016213:Cyclins / Q000502:physiology; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D008954:Models, Biological; D016160:Retinoblastoma Protein / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D025521:Tumor Suppressor Proteins; D018631:ras Proteins / Q000502:physiology*; D020741:rho GTP-Binding Proteins / Q000502:physiology*
C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016160:Retinoblastoma Protein; D025521:Tumor Suppressor Proteins; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases; D018631:ras Proteins; D020741:rho GTP-Binding Proteins