Abstract
It is not known how the protein Bcl-2 inhibits cell death induced by calcium signalling and growth-factor withdrawal. Here we report that Bcl-2 forms a tight complex with calcineurin, resulting in the targeting of calcineurin to Bcl-2 sites on cytoplasmic membranes, and show that this interaction is dependent on the BH4 domain of Bcl-2. Calcineurin bound to Bcl-2 is an active phosphatase but is unable to promote the nuclear translocation of NF-AT, a transcription-factor required for induction of interleukin-2 expression, suggesting a mechanism by which Bcl-2 suppresses NF-AT activity. We also show that Bax, a pro-apoptotic member of the Bcl-2 family, interferes with interactions between calcineurin and Bcl-2. We propose that the ability of Bcl-2 to block NF-AT signalling is due to the sequestering of active calcineurin to the same domain of Bcl-2 which associates with Rad-1 (ref. 5), and that calcineurin may act in Bcl-2-regulated functions.
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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Amino Acid Sequence
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Animals
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B-Lymphocytes / metabolism
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Binding Sites
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Biological Transport
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Calcineurin
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Calmodulin-Binding Proteins / metabolism*
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Cell Line
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Cell Nucleus / metabolism
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Consensus Sequence
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Cricetinae
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DNA-Binding Proteins / antagonists & inhibitors*
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DNA-Binding Proteins / metabolism
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Humans
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Intracellular Membranes / metabolism
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Molecular Sequence Data
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NFATC Transcription Factors
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Nuclear Proteins*
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Phosphoprotein Phosphatases / metabolism*
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Protein Binding
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-bcl-2 / metabolism*
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Sequence Alignment
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Signal Transduction*
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T-Lymphocytes / metabolism
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Transcription Factors / antagonists & inhibitors*
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Transcription Factors / metabolism
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bcl-2-Associated X Protein
Substances
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BAX protein, human
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Calmodulin-Binding Proteins
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DNA-Binding Proteins
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NFATC Transcription Factors
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Nuclear Proteins
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Transcription Factors
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bcl-2-Associated X Protein
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Calcineurin
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Phosphoprotein Phosphatases