ACTIVATION OF CYCLIN-DEPENDENT KINASE 2 (CDK2) IN GROWTH-STIMULATED RAT ASTROCYTES - GERANYLGERANYLATED RHO SMALL GTPASE(S) ARE ESSENTIAL FOR THE INDUCTION OF CYCLIN-E GENE-EXPRESSION

The role of the mevalonate cascade in the control of cell cycle progre ssion in astrocytes has been investigated. Serum stimulation of rat as trocytes in primary culture induces the expression of cyclin E followe d by the activation of cyclin-dependent kinase 2 (Cdk2) during G(1)/S transition. The expression of p27(hip1) cyclin D1, and the activities of Cdk4 and Cdk-activating kinase (CAB), composed of Cdk7 and cyclin H , mere not affected. Serum did, however, stimulate the expression of 3 -hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase mRNA at mid-G(1) pha se. Moreover, an inhibitor of HMG-CoA reductase, pravastatin, reduced cyclin E expression and Cdk2 activation and caused G(1) arrest in the astro cytes. In contrast, mevalonate and its metabolite, geranylgerany lpyrophosphate (GGPP) but not farnesylpyrophosphate (FPP), reversed th e inhibitory effects of pravastatin on cyclin E expression and Cdk2 ac tivation and allowed G(1)/S transition. Rho small GTPase(s) were geran ylgeranylated and translocated to membranes in the presence of GGPP du ring G(1)/S transition. The effect of GGPP on cyclin E expression was abolished by botulinum C3 exoenzyme, which specifically inactivates Rh o. These data indicate that geranylgeranylated Rho small GTPase(s) are essential for the induction of cyclin E expression, Cdk2 activation, and G(1)/S transition in rat astrocytes.