Rac and Cdc42 Are Potent Stimulators of E2F-dependent Transcription Capable of Promoting Retinoblastoma

The Rho family of GTPases plays an important and diverse role in reorganization of the actin cytoskeleton, transcriptional regulation, and multiple aspects of cell growth. Our study has examined their potential links to the cell cycle machinery. We find that constitutively active mutants of Rac and Cdc42, but not Rho, are po-tent inducers of E2F transcriptional activity in NIH 3T3 fibroblasts. Furthermore, activated Rac and Cdc42, but again not Rho, are capable of inducing cyclin D1 accu-mulation and pRB hyperphosphorylation in serum-de-prived cells, outlining one route leading to enhanced E2F-mediated transcription. The inhibitory effect of the cyclin-dependent kinase inhibitors, p16ink4, p21cip1, and p27cip on Rac/Cdc42-mediated E2F transcription corrob-orates a role for pRB family members and their func