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 terminal differentiation. The subversion of these anti-neoplastic effects during Ras-dependent tumor development may be as important as the acquisition of the pro-neoplastic effects. None of the currently identified potential Ras effector proteins can satisfactorily explain the apoptotic action of Ras. Consequently, we have sought to identify novel Ras effectors that may be responsible for apoptosis induction. By examining the EST data base, we identified a potential Ras association domain in the tumor suppressor RASSF1. We now show that RASSF1 binds Ras in a GTP-dependent manner, both in vivo and directly in vitro. Moreover, activated Ras enhances and dominant negative Ras 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-transfected 293-T cells exhibit membrane blebbing and can be rescued by the addition of a caspase inhibitor. Thus, the RASSF1 tumor suppressor may serve as a novel Ras effector that mediates the apoptotic effects of oncogenic Ras.
Vos
M D
MD
Department of Cell and Cancer Biology, NCI, National Institutes of Health, Rockville, Maryland 20850-3300, USA.
Ellis
C A
CA
Bell
A
A
Birrer
M J
MJ
Clark
G J
GJ
D016475:3T3 Cells; D017398:Alternative Splicing / Q000235:genetics; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D061945:Caspase Inhibitors; D015536:Down-Regulation; D005260:Female; D016147:Genes, Tumor Suppressor / Q000235:genetics*; D006160:Guanosine Triphosphate / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D011993:Recombinant Fusion Proteins; D014162:Transfection; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D009363:Neoplasm Proteins; C411762:RASSF1 protein, human; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D025521:Tumor Suppressor Proteins; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D006160:Guanosine Triphosphate; D018631:ras Proteins