title: The tumor suppressor RASSF1A and MAP-1 link death receptor signaling to Bax conformational change and cell death.
abstract: 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.
authors.affiliation: 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
authors.forename: Shairaz
authors.initials: S
authors.lastname: Baksh
authors.forename: Stella
authors.initials: S
authors.lastname: Tommasi
authors.forename: Sarah
authors.initials: S
authors.lastname: Fenton
authors.forename: Victor C
authors.initials: VC
authors.lastname: Yu
authors.forename: L Miguel
authors.initials: LM
authors.lastname: Martins
authors.forename: Gerd P
authors.initials: GP
authors.lastname: Pfeifer
authors.forename: Farida
authors.initials: F
authors.lastname: Latif
authors.forename: Julian
authors.initials: J
authors.lastname: Downward
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Neel
mesh_terms: 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
chemical_list: 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