Abstract
Although Ras is a potent oncogene in human tumors it has the paradoxical ability to promote Oncogene Induced Senescence (OIS). This appears to serve as a major barrier to Ras driven transformation in vivo. The signaling pathways used by Ras to promote senescence remain relatively poorly understood, but appear to invoke both the p53 and the Rb master tumor suppressors. Exactly how Ras communicates with p53 and Rb has remained something of a puzzle. NORE1A is a direct Ras effector that is frequently downregulated in human tumors. We have now found that it serves as a powerful Ras senescence effector. Moreover, we have defined signaling mechanisms that allows Ras to control both p53 and Rb post-translational modifications via the NORE1A scaffolding molecule. Indeed, NORE1A can be detected in complex with both p53 and Rb. Thus, by coupling Ras to both tumor suppressors, NORE1A forms a major component of the Ras senescence machinery and serves as the missing link between Ras and p53/Rb.