AI Article Synopsis
- RASSF1A is a tumor suppressor that is often silenced in tumors due to promoter methylation, affecting important cellular functions like cell cycle regulation and apoptosis.
- The study reveals a new pathway where RASSF1A interacts with the protein MOAP-1, which is crucial for activating Bax, a protein that promotes cell death, particularly when K-Ras is activated.
- Tumor-derived mutations in RASSF1A disrupt its interaction with MOAP-1 and impair Bax activation, highlighting a critical pro-apoptotic pathway involving K-Ras, RASSF1A, and Bax that is compromised in some cancers.
Article Abstract
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.
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| http://dx.doi.org/10.1074/jbc.M512128200 | DOI Listing |
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