MYC AND RAS COLLABORATE IN INDUCING ACCUMULATION OF ACTIVE CYCLIN E CDK2 AND E2F/

Considerable evidence points to a role for G1 cyclin-dependent kinase (CDK) in allowing the accumulation of E2F transcription factor activit y and induction of the S phase of the cell cycle(1,2). Numerous experi ments have also demonstrated a critical role for both Myc and Ras acti vities in allowing cell-cycle progression(3). Here we show that inhibi tion of pas activity blocks the normal growth-dependent activation of G1 CDK, prevents activation of the target genes of E2F, and results in cell-cycle arrest in G1. We also show that Ras is essential for entry into the S phase in Rb+/+ fibroblasts but not in Rb-/- fibroblasts, e stablishing a link between Ras and the G1 CDK/Rb/E2F pathway, However, although expression of pas alone will not induce G1 CDK activity or S phase, coexpression of Ras with Myc allows the generation of cyclin E -dependent kinase activity and the induction of S phase, coincident wi th the loss of the p27 cyclin-dependent kinase inhibitor (CKI). These results suggest that pas, along with the activation of additional path ways, is required for the generation of G1 CDK activity, and that acti vation of cyclin E-dependent kinase in particular depends on the coope rative action of Ras and Myc.