The Tumor Suppressor, RASSF1A and MAP-1 Link Death Receptor Signaling to Bax Conformational Change and Cell Death

S Baksh, S Tommasi, Sarah Fenton, V Yu, M Martins, G Pfeifer, Farida Latif, J Downward, BG Neel

    Research output: Contribution to journalArticle

    138 Citations (Scopus)

    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.
    Original languageEnglish
    Pages (from-to)637-650
    Number of pages14
    JournalMolecular Cell
    Volume18
    DOIs
    Publication statusPublished - 10 Jun 2005

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