Abstract
Nuclear import of the NF-AT transcription factors during T-cell activation requires the calcium-activated phosphatase calcineurin, which unmasks nuclear-location signals on NF-AT. We show here that the nuclear import of NF-ATs is not sufficient to activate NF-AT target genes, as NF-ATs are subject to a futile cycling across the nuclear envelope owing to engagement with the exportin protein Crm1. Calcineurin suppresses this futile cycling by a non-catalytic mechanism involving the masking of nuclear export signals on NF-AT targeted by Crm1. This clustering of binding sites for calcineurin and Crml on NF-AT establishes an inherent competition between these molecules that imparts exquisite calcium sensitivity to the shuttling dynamics of the NF-AT transcription factors. Such a balance between nuclear import and export may regulate the action of other transcription factors.
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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Animals
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Binding Sites
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Biological Transport
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Calcineurin / metabolism*
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Calcium / metabolism
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Calcium Signaling
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Carrier Proteins / antagonists & inhibitors
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Carrier Proteins / metabolism*
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Cell Nucleus / metabolism
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Cricetinae
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DNA-Binding Proteins / antagonists & inhibitors
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Enzyme Activation
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Exportin 1 Protein
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HeLa Cells
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Humans
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Hybrid Cells
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Karyopherins*
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Mutation
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NFATC Transcription Factors
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Nuclear Localization Signals
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Nuclear Proteins*
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Precipitin Tests
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Receptors, Cytoplasmic and Nuclear*
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Transcription Factors / antagonists & inhibitors
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transcriptional Activation
Substances
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Carrier Proteins
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DNA-Binding Proteins
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Karyopherins
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NFATC Transcription Factors
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Nuclear Localization Signals
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Nuclear Proteins
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Receptors, Cytoplasmic and Nuclear
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Transcription Factors
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Calcineurin
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Calcium