COOPERATING ONCOGENES CONVERGE TO REGULATE CYCLIN CDK COMPLEXES/

The cooperation of oncogenes in the transformation of primary rat Schw ann cells is a strikingly synergistic process. We have explored the mo lecular mechanisms involved. Activation of an inducible Raf kinase res ults in morphologically transformed cells that are arrested in G(1), v ia the induction of p21(Cip1) and subsequent inhibition of cyclin/cdk activity. In contrast, coexpression of SV40 large T (LT) or a dominant -negative mutant of p53 abolishes p21(Cip1) induction and alleviates t he growth arrest. Moreover in this scenario, Raf activation results in an increase in the specific activity of cyclin/cdk complexes with Raf and LT cooperating to superinduce cyclin A/cdk2 activity and stimulat e proliferation in the absence of mitogens. Thus, signaling by Raf and its cooperating partners converges at the regulation of cyclin/cdk co mplexes, with the cellular responses to Raf modulated by p53.