Abstract
The NF-AT family of transcription factors participates in the regulation of early immune response genes such as IL-2, IL-4, CD40 ligand, and Fas ligand in response to Ca2+/calcineurin signals initiated at the antigen receptor. Calcineurin activation leads to the rapid translocation of NF-AT family members from cytoplasm to nucleus, an event that is blocked by the immunosuppressive drugs cyclosporin A and FK506. We show that translocation requires two redundant nuclear localization sequences and that one sequence is in an intramolecular association with phosphorserines in a conserved motif located at the amino terminus of each NF-AT protein. Mutation of serines in this motif in NF-ATc both disrupts this intramolecular interaction and leads to nuclear localization, suggesting a model of NF-AT nuclear import in which dephosphorylation by calcineurin causes exposure of two nuclear localization sequences.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Biological Transport / drug effects
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COS Cells
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Calcineurin
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Calcium / metabolism
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Calmodulin-Binding Proteins / metabolism*
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Cell Compartmentation / drug effects*
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Cell Nucleus
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Cyclosporine / pharmacology*
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Cytoplasm
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DNA-Binding Proteins / metabolism*
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Immunosuppressive Agents / pharmacology*
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Molecular Sequence Data
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NFATC Transcription Factors
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Nuclear Proteins / metabolism*
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Phosphoprotein Phosphatases / metabolism*
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Phosphorylation
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Phosphoserine / metabolism
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Recombinant Proteins / metabolism
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Sequence Homology, Amino Acid
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Serine / genetics
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Serine / metabolism
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Structure-Activity Relationship
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Tacrolimus / pharmacology
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Transcription Factors / metabolism*
Substances
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Calmodulin-Binding Proteins
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DNA-Binding Proteins
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Immunosuppressive Agents
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NFATC Transcription Factors
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Nuclear Proteins
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Recombinant Proteins
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Transcription Factors
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Phosphoserine
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Serine
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Cyclosporine
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Calcineurin
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Phosphoprotein Phosphatases
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Calcium
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Tacrolimus