TY - JOUR
T1 - The Tumor Suppressor, RASSF1A and MAP-1 Link Death Receptor Signaling to Bax Conformational Change and Cell Death
AU - Baksh, S
AU - Tommasi, S
AU - Fenton, Sarah
AU - Yu, V
AU - Martins, M
AU - Pfeifer, G
AU - Latif, Farida
AU - Downward, J
AU - Neel, BG
PY - 2005/6/10
Y1 - 2005/6/10
N2 - 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. TNFalpha 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.
AB - 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. TNFalpha 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.
UR - http://www.scopus.com/inward/record.url?scp=20444414891&partnerID=8YFLogxK
U2 - 10.1016/j.molcel.2005.05.010
DO - 10.1016/j.molcel.2005.05.010
M3 - Article
C2 - 15949439
VL - 18
SP - 637
EP - 650
JO - Molecular Cell
JF - Molecular Cell
ER -