Ras regulates Rb via NORE1A [Signal Transduction]

December 16th, 2015 by Barnoud, T., Donninger, H., Clark, G. J.

Mutations in the Ras oncogene are one of the most frequent events in human cancer. While Ras regulates numerous growth promoting pathways to drive transformation, it can paradoxically promote an irreversible cell cycle arrest known as oncogene induced senescence. Though senescence has clearly been implicated as a major defense mechanism against tumorigenesis, the mechanisms by which Ras can promote such a senescent phenotype remain poorly defined. We have recently shown that the Ras death effector NORE1A plays a critical role in promoting Ras induced senescence and connects Ras to the regulation of the p53 tumor suppressor. We now show that NORE1A also connects Ras to the regulation of a second major pro-senescent tumor suppressor, the Retinoblastoma (Rb) protein. We show that Ras induces the formation of a complex between NORE1A and the phosphatase PP1A, promoting the activation of the Rb tumor suppressor by dephosphorylation. Furthermore, suppression of Rb reduces NORE1A senescence activity. These results, together with our previous findings, suggest that NORE1A acts as a critical tumor suppressor node linking Ras to both the p53 and the Rb pathways in order to drive senescence.