Abstract
The immunosuppressant drug cyclosporin A blocks a calcium-dependent signal from the T-cell receptor (TCR) that normally leads to T-cell activation. When bound to cyclophilin, cyclosporin A binds and inactivates the key signalling intermediate calcineurin. To identify potential cellular homologues of cyclosporin A that might regulate calcium signalling, we have cloned human genes encoding cyclophilin B-binding-proteins using the yeast two-hybrid system. One gene product, when overexpressed in Jurkat T cells, specifically induced transcription from the interleukin-2 enhancer, by activating the T-cell-specific transcription factors NF-AT and NF-IL2A. This protein, termed calcium-signal modulating cyclophilin ligand (CAML), acts downstream of the TCR and upstream of calcineurin by causing an influx of calcium. CAML appears to be a new participant in the calcium-signal transduction pathway, implicating cyclophilin B in calcium signalling, even in the absence of cyclosporin.
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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Adaptor Proteins, Signal Transducing*
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Amino Acid Isomerases / metabolism*
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Amino Acid Sequence
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Base Sequence
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Calcium / metabolism*
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Cell Line
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Cloning, Molecular
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Cyclophilins*
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Cyclosporine / pharmacology
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DNA
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DNA-Binding Proteins / metabolism
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Humans
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Lymphocyte Activation
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Molecular Sequence Data
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Mutation
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NFATC Transcription Factors
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Nuclear Proteins*
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Peptidylprolyl Isomerase
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Protein Kinase C / metabolism
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RNA, Messenger / metabolism
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Signal Transduction*
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T-Lymphocytes / drug effects
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T-Lymphocytes / immunology
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T-Lymphocytes / metabolism*
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Tacrolimus / pharmacology
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Transcription Factors / metabolism
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Transcription, Genetic
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Transfection
Substances
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Adaptor Proteins, Signal Transducing
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CAMLG protein, human
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Carrier 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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RNA, Messenger
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Transcription Factors
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cyclophilin B
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Cyclosporine
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DNA
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Protein Kinase C
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Amino Acid Isomerases
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Cyclophilins
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Peptidylprolyl Isomerase
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Calcium
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Tacrolimus