RAS LINKS GROWTH-FACTOR SIGNALING TO THE CELL-CYCLE MACHINERY VIA REGULATION OF CYCLIN D1 AND THE CDK INHIBITOR P27(KIP1)

Activation of growth factor receptors by ligand binding initiates a ca scade of events leading to cell growth and division. Progression throu gh the fell cycle is controlled by cyclin-dependent protein kinases (C dks), but the mechanisms that link growth factor signaling to the cell cycle machinery have not been established, We report here that Ras pr oteins play a key role in integrating mitogenic signals with cell cycl e progression through G(I). Ras is required for cell cycle progression and activation of both Cdk2 and Cdk4 until similar to 2 h before the G(I)/S transition, corresponding to the restriction point, Analysis of Cdk-cyclin complexes indicates that Res signaling is required both fo r induction of cyclin D1 and for downregulation of the Cdk inhibitor p 27(KIP1). Constitutive expression of cyclin D1 circumvents the require ment for Bas signaling in cell proliferation, indicating that regulati on of cyclin D1 is a critical target of the Res signaling cascade.