The Ras Effector RASSF2 Controls the PAR-4 Tumor Suppressor

Abstract

RASSF2 is a novel proapoptotic effector of K-Ras. Inhibition of RASSF2 expression enhances the transforming effects of K-Ras, and epigenetic inactivation of RASSF2 is frequently detected in mutant Ras-containing primary tumors. Thus, RASSF2 is implicated as a tumor suppressor whose inactivation facilitates transformation by disconnecting apoptotic responses from Ras. The mechanism of action of RASSF2 is not known. Here we show that RASSF2 forms a direct and endogenous complex with the prostate apoptosis response protein 4 (PAR-4) tumor suppressor. This interaction is regulated by K-Ras and is essential for the full apoptotic effects of PAR-4. RASSF2 is primarily a nuclear protein, and shuttling of PAR-4 from the cytoplasm to the nucleus is essential for its function. We show that RASSF2 modulates the nuclear translocation of PAR-4 in prostate tumor cells, providing a mechanism for its biological effects. Thus, we identify the first tumor suppressor signaling pathway emanating from RASSF2, we identify a novel mode of action of a RASSF protein, and we provide an explanation for the extraordinarily high frequency of RASSF2 inactivation we have observed in primary prostate tumors.

We thank Vivek Rangnekar (University of Kentucky, Lexington) for reagents and advice, Manuel Serrano and Pablo Fernandez-Marcos (Spanish National Cancer Research Center) for unpublished negative data, and Nina Niessl and Monika Kerscher for excellent technical assistance in processing the tissue specimens.

This work was funded in part by NIH grant 1P20 RR18733, NCI intramural funds (G.J.C.), and the Breast Cancer Campaign, Cancer Research UK (F.L.).