Vos Michele D, Dallol Ashraf, Eckfeld Kristin, Allen Nadia P C, Donninger Howard, Hesson Luke B, Calvisi Diego, Latif Farida, Clark Geoffrey J
Department of Cell and Cancer Biology, NCI, National Institutes of Health, Rockville, Maryland 20850-3300, USA.
J Biol Chem. 2006 Feb 24;281(8):4557-63. doi: 10.1074/jbc.M512128200. Epub 2005 Dec 12.
The novel tumor suppressor RASSF1A is frequently inactivated during human tumorigenesis by promoter methylation. RASSF1A may serve as a node in the integration of signaling pathways controlling a range of critical cellular functions including cell cycle, genomic instability, and apoptosis. The mechanism of action of RASSF1A remains under investigation. We now identify a novel pathway connecting RASSF1A to Bax via the Bax binding protein MOAP-1. RASSF1A and MOAP-1 interact directly, and this interaction is enhanced by the presence of activated K-Ras. RASSF1A can activate Bax via MOAP-1. Moreover, activated K-Ras, RASSF1A, and MOAP-1 synergize to induce Bax activation and cell death. Analysis of a tumor-derived point mutant of RASSF1A showed that the mutant was defective for the MOAP-1 interaction and for Bax activation. Moreover, inhibition of RASSF1A by shRNA impaired the ability of K-Ras to activate Bax. Thus, we identify a novel pro-apoptotic pathway linking K-Ras, RASSF1A and Bax that is specifically impaired in some human tumors.
新型肿瘤抑制因子RASSF1A在人类肿瘤发生过程中常因启动子甲基化而失活。RASSF1A可能作为信号通路整合的节点，控制包括细胞周期、基因组不稳定性和细胞凋亡在内的一系列关键细胞功能。RASSF1A的作用机制仍在研究中。我们现在鉴定出一条通过Bax结合蛋白MOAP-1将RASSF1A与Bax相连的新途径。RASSF1A与MOAP-1直接相互作用，且这种相互作用在活化的K-Ras存在时增强。RASSF1A可通过MOAP-1激活Bax。此外，活化的K-Ras、RASSF1A和MOAP-1协同诱导Bax活化和细胞死亡。对RASSF1A肿瘤来源的点突变体分析表明，该突变体在MOAP-1相互作用和Bax活化方面存在缺陷。此外，shRNA对RASSF1A的抑制损害了K-Ras激活Bax的能力。因此，我们鉴定出一条连接K-Ras、RASSF1A和Bax的新的促凋亡途径，该途径在某些人类肿瘤中特异性受损。
