The Ras effector RASSF2 controls the PAR-4 tumor suppressor.
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.
Donninger
Howard
H
Department of Medicine, James Graham Brown Cancer Center, Molecular Targets Program, University of Louisville, 505 S. Hancock St., Louisville, KY 40202, USA.
Hesson
Luke
L
Vos
Michele
M
Beebe
Kristin
K
Gordon
Laura
L
Sidransky
David
D
Liu
Jun Wei
JW
Schlegel
Thomas
T
Payne
Shannon
S
Hartmann
Arndt
A
Latif
Farida
F
Clark
Geoffrey J
GJ
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D011905:Genes, ras; D006801:Humans; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D011467:Prostate / Q000166:cytology / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D020798:Two-Hybrid System Techniques; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C425300:RASSF2 protein, human; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D025521:Tumor Suppressor Proteins; C101296:prostate apoptosis response-4 protein; D018631:ras Proteins