Cloning and characterization of NF-ATc and NF-ATp: the cytoplasmic components of NF-AT.
Present evidence indicates a pathway of signal transmission in T cells that is outlined in figure 1. The elevation in intracellular calcium that is induced by interactions at the antigen receptor leads to the activation of the calcium-dependent phosphatase calcineurin. This in turn leads to the nuclear association of the cytosolic component of NF-ATc. The activation of calcineurin and the nuclear import of NF-ATc can both be blocked by cyclosporin A or FK506 in complex with their respective immunophilins. Once in the nucleus, NF-ATc interacts with NF-ATn to form an active transcriptional complex. NF-ATn is a ubiquitous protein, can be synthesized in response to PMA, and has many similarities to AP-1. The mechanism by which NF-ATc enters the nucleus is unknown, and although it appears to require calcineurin, NF-ATc has not yet been shown to be an in vivo substrate of calcineurin. Alternative mechanisms include the possibility that NF-ATc operates on some cytoplasmic anchor or that other proteins that are controlled by calcineurin carry out the nuclear import of NF-ATc. Although NF-ATp copurifies with NF-ATc, there is as yet no understanding of how NF-ATp is functioning in vivo. Now that these proteins are purified and cloned, the major goals will be to understand their role and the roles of other family members in thymic development.
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Department of Pathology, Howard Hughes Medical Institute, Stanford University School of Medicine, CA 94305-5428.
Timmerman
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Northrop
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Crabtree
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D000818:Animals; D001665:Binding Sites; D019703:Calcineurin; D002148:Calmodulin-Binding Proteins / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000302:isolation & purification*; D006801:Humans; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism*; D013950:Thymus Gland / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry / Q000302:isolation & purification*
D002148:Calmodulin-Binding Proteins; D004268:DNA-Binding Proteins; D050778:NFATC Transcription Factors; C494006:NFATC2 protein, human; D009687:Nuclear Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D019703:Calcineurin; D010749:Phosphoprotein Phosphatases