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 cascade of events leading to cell growth and division. Progression through the fell cycle is controlled by cyclin-dependent protein kinases (Cdks), but the mechanisms that link growth factor signaling to the cell cycle machinery have not been established, We report here that Ras proteins play a key role in integrating mitogenic signals with cell cycle 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 for induction of cyclin D1 and for downregulation of the Cdk inhibitor p27(KIP1). Constitutive expression of cyclin D1 circumvents the requirement for Bas signaling in cell proliferation, indicating that regulation of cyclin D1 is a critical target of the Res signaling cascade.