The role of bim, a proapoptotic BH3-only member of the Bcl-2 family in cell-death control.
Apoptosis is an evolutionarily conserved process for killing unwanted cells. Genetic and biochemical experiments have indicated that three groups of proteins are necessary for activation of the cell-death effector machinery: cysteine proteases, their adaptors, and proapoptotic Bcl-2 family members. Antiapoptotic Bcl-2 family members are needed for cell survival. We have cloned Bim, a proapoptotic Bcl-2 family member that shares with the family only a 9-16 aa region of homology [Bcl-3 homology region(BH3)], but is otherwise unique. Bim requires its BH3 region for binding to Bcl-2 and activation of apoptosis. Analysis of Bim-deficient mice has shown that Bim is essential for the execution of some but not all apoptotic stimuli that can be antagonized by Bcl-2. Bim-deficient mice have increased numbers of lymphocytes, plasma cells, and myeloid cells, and most develop fatal autoimmune glomerulonephritis. In healthy cells, Bim is bound to the microtubule-associated dynein motor complex, and is thereby sequestered from Bcl-2. Certain apoptotic signals unleash Bim and allow it to translocate to intracellular membranes, where it interacts with Bcl-2 or its homologues. These results indicate that BH3-only proteins are essential inducers of apoptosis that can be unleashed by certain death signals. Unleashed BH3-only proteins neutralize the prosurvival function of Bcl-2-like molecules, and this is thought to liberate Apaf-l-like adapters to activate caspase zymogens, which then initiate cell degradation.
Strasser
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Walter and Eliza Hall Institute, Post Office Royal Melbourne Hospital, 3050 Vic., Melbourne, Australia. strasser@wehi.edu.au
Puthalakath
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Bouillet
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Huang
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O'Connor
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O'Reilly
L A
LA
Cullen
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L
Cory
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Adams
J M
JM
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology*; D019254:Genes, bcl-2 / Q000502:physiology*; D006801:Humans