Ras uses the novel tumor suppressor RASSF1 as an effector to mediate apoptosis

Although activated Ras proteins are usually associated with driving growth and transformation, they may also induce senescence, apoptosis, and termina l differentiation. The subversion of these anti-neoplastic effects during R as-dependent tumor development may be as important as the acquisition of th e pro-neoplastic effects. None of the currently identified potential Ras ef fector proteins can satisfactorily explain the apoptotic action of Ras. Con sequently, we have sought to identify novel Ras effecters that may be respo nsible for apoptosis induction. By examining the EST data base, we identifi ed a potential. Ras association domain in the tumor suppressor RASSF1. We n ow show that RASSF1 binds Ras in a GTP-dependent manner, both in vivo and d irectly in vitro. Moreover, activated Ras enhances and dominant negative Ra s inhibits the cell death induced by transient transfection of RASSF1 into 293-T cells. This cell death appears to be apoptotic in nature, as RASSF1-t ransfected 293-T cells exhibit membrane blebbing and can be rescued by the addition of a caspase inhibitor. Thus, the RASSF1 tumor suppressor may serv e as a novel Ras effector that mediates the apoptotic effects of oncogenic Ras.