Induction of BIM, a proapoptotic BH3-only BCL-2 family member, is critical for neuronal apoptosis |
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Authors: | Putcha G V Moulder K L Golden J P Bouillet P Adams J A Strasser A Johnson E M |
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Institution: | Departments of Neurology and Molecular Biology & Pharmacology, Washington University School of Medicine, Saint Louis, MO 63110, USA. |
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Abstract: | Sympathetic neuronal death induced by nerve growth factor (NGF) deprivation requires the macromolecular synthesis-dependent translocation of BAX from the cytosol to mitochondria and its subsequent integration into the mitochondrial outer membrane, followed by BAX-mediated cytochrome c (cyt c) release. The gene products triggering this process remain unknown. Here, we report that BIM, a member of the BH3-only proapoptotic subfamily of the BCL-2 protein family, is one such molecule. NGF withdrawal induced expression of BIM(EL), an integral mitochondrial membrane protein that functions upstream of (or in parallel with) the BAX/BCL-2 and caspase checkpoints. Bim deletion conferred protection against developmental and induced neuronal apoptosis in both central and peripheral populations, but only transiently, suggesting that BIM--and perhaps other BH3-only proteins--serve partially redundant functions upstream of BAX-mediated cyt c release. |
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