Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD

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...

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Bibliographic Details
Published in:Science (American Association for the Advancement of Science) 1999-04, Vol.284 (5412), p.339-343
Main Authors: WANG, H.-G, PATHAN, N, ETHELL, I. M, KRAJEWSKI, S, YAMAGUCHI, Y, SHIBASAKI, F, MCKEON, F, BOBO, T, FRANKE, T. F, REED, J. C
Format: Article
Language:English
Subjects:
14-3-3 Proteins
Ageing, cell death
Animals
Apoptosis
bcl-Associated Death Protein
bcl-X Protein
Biological and medical sciences
Calcineurin - genetics
Calcineurin - metabolism
Calcineurin Inhibitors
Calcium - metabolism
Calcium - pharmacology
Carrier Proteins - chemistry
Carrier Proteins - metabolism
Cell Line
Cell physiology
Cells, Cultured
Dimerization
Enzyme Inhibitors - pharmacology
Fundamental and applied biological sciences. Psychology
Glutamic Acid - pharmacology
Hippocampus - cytology
Humans
Mitochondria - metabolism
Molecular and cellular biology
Neurons - cytology
Neurons - metabolism
Phosphorylation
Protein-Serine-Threonine Kinases - metabolism
Proteins - metabolism
Proto-Oncogene Proteins c-bcl-2 - metabolism
Rats
Recombinant Fusion Proteins - metabolism
Transfection
Tyrosine 3-Monooxygenase
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Summary: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.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.284.5412.339