The tumor suppressor RASSF1A and MAP-1 link death receptor signaling to Bax conformational change and cell death.
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.
Baksh
Shairaz
S
Cancer Biology Program, Division of Hematology and Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, 1038 NRB, 330 Brookline Avenue, Boston, Massachusetts 02215, USA. sbaksh@bidmc.harvard.edu
Tommasi
Stella
S
Fenton
Sarah
S
Yu
Victor C
VC
Martins
L Miguel
LM
Pfeifer
Gerd P
GP
Latif
Farida
F
Downward
Julian
J
Neel
Benjamin G
BG
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D001943:Breast Neoplasms; D016923:Cell Death; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology*; D045304:Cytochromes c / Q000032:analysis; D005260:Female; D017353:Gene Deletion; D006801:Humans; D007425:Intracellular Membranes / Q000502:physiology; D008928:Mitochondria / Q000502:physiology; D011487:Protein Conformation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry* / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D051028:bcl-2-Associated X Protein
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C494826:BAX protein, human; C428449:MOAP1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; C411762:RASSF1 protein, human; D025521:Tumor Suppressor Proteins; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c