Journal
MOLECULAR CELL
Volume 18, Issue 6, Pages 637-650Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2005.05.010
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Funding
- Medical Research Council [MC_U132674518] Funding Source: Medline
- NCI NIH HHS [R37CA49152] Funding Source: Medline
- Breast Cancer Now [1999:98] Funding Source: Medline
- MRC [MC_U132674518] Funding Source: UKRI
- Medical Research Council [MC_U132674518] Funding Source: researchfish
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Tumor cells typically resist programmed cell death (apoptosis) induced by death receptors. Activated death receptors evoke Bax conformational change cytochrome c release, and cell death. We report that the tumor suppressor gene RASSF1A is required for death receptor-induced Bax conformational change and apoptosis. TNF alpha or TRAIL stimulation induced recruitment of RASSF1A and MAP-1 to receptor complexes and promoted complex formation between RASSF1A and the BH3-like protein MAP-1. Normally, MAP-1 is inhibited by an intramolecular interaction. RASSF1A/MAP-1 binding relieved this inhibitory interaction, resulting in MAP-1 association with Bax. Deletion of the RASSF1A gene or short hairpin silencing of either RASSF1A or MAP-1 expression blocked MAP-1/Bax interaction, Bax conformational change and mitochondrial membrane insertion, cytochrome c release, and apoptosis in response to death receptors. Our findings identify RASSF1A and MAP-1 as important components between death receptors and the apoptotic machinery and reveal a potential link between tumor suppression and death receptor signaling.
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