Abstract
The Ca2+-activated protein phosphatase calcineurin induces apoptosis, but the mechanism is unknown. Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis. The Ca2+-induced dephosphorylation of BAD correlated with its dissociation from 14-3-3 in the cytosol and translocation to mitochondria where Bcl-xL resides. In hippocampal neurons, L-glutamate, an inducer of Ca2+ influx and calcineurin activation, triggered mitochondrial targeting of BAD and apoptosis, which were both suppressible by coexpression of a dominant-inhibitory mutant of calcineurin or pharmacological inhibitors of this phosphatase. Thus, a Ca2+-inducible mechanism for apoptosis induction operates by regulating BAD phosphorylation and localization in cells.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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14-3-3 Proteins
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Animals
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Apoptosis*
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Calcineurin / genetics
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Calcineurin / metabolism*
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Calcineurin Inhibitors
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Calcium / metabolism*
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Calcium / pharmacology
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Carrier Proteins / chemistry
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Carrier Proteins / metabolism*
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Cell Line
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Cells, Cultured
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Dimerization
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Enzyme Inhibitors / pharmacology
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Glutamic Acid / pharmacology
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Hippocampus / cytology
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Humans
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Mitochondria / metabolism
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Neurons / cytology
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Neurons / metabolism
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Phosphorylation
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Protein Serine-Threonine Kinases / metabolism
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Proteins / metabolism
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Rats
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Recombinant Fusion Proteins / metabolism
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Transfection
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Tyrosine 3-Monooxygenase*
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bcl-Associated Death Protein
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bcl-X Protein
Substances
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14-3-3 Proteins
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BAD protein, human
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BCL2L1 protein, human
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Bad protein, rat
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Bcl2l1 protein, rat
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Calcineurin Inhibitors
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Carrier Proteins
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Enzyme Inhibitors
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Proteins
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Proto-Oncogene Proteins c-bcl-2
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Recombinant Fusion Proteins
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bcl-Associated Death Protein
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bcl-X Protein
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Glutamic Acid
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Tyrosine 3-Monooxygenase
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Protein Serine-Threonine Kinases
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Calcineurin
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Calcium