Calcineurin acts in synergy with PMA to inactivate I kappa B/MAD3, an inhibitor of NF-kappa B
| Autor: | R.L. Kincaid, E.C. Nordby, N. Steffan, Edward A. O'Neill, Michael J. Tocci, G D Bren, Stephen J. O'Keefe, C.V. Paya, Betsy Frantz |
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| Rok vydání: | 1994 |
| Předmět: |
T-Lymphocytes
Molecular Sequence Data Phosphatase Biology DNA-binding protein General Biochemistry Genetics and Molecular Biology NF-KappaB Inhibitor alpha Proto-Oncogene Proteins Cyclosporin a Phosphoprotein Phosphatases Humans Molecular Biology Transcription factor Cells Cultured Base Sequence General Immunology and Microbiology Calcineurin General Neuroscience Transcription Factor RelB T-cell receptor NF-kappa B Drug Synergism Promoter DNA NFKB1 Molecular biology DNA-Binding Proteins Oligodeoxyribonucleotides Tetradecanoylphorbol Acetate Calmodulin-Binding Proteins I-kappa B Proteins Transcription Factors Research Article |
| Zdroj: | The EMBO Journal. 13:861-870 |
| ISSN: | 0261-4189 |
| DOI: | 10.1002/j.1460-2075.1994.tb06329.x |
| Popis: | The interleukin-2 (IL-2) promoter consists of several independent T cell receptor (TcR) responsive elements. The induction of promoters dependent on these elements is inhibitable by the immunosuppressants cyclosporin A (CsA) and tacrolimus (FK-506). Calcineurin, a Ca2+/calmodulin-dependent protein phosphatase, is the FK-506- and CsA-sensitive enzyme required for TcR mediated activation of the IL-2 promoter. We report that a constitutively active form of calcineurin partially substitutes for the Ca2+ co-stimulus required to activate the IL-2 promoter elements IL-2A (which binds the factors OAP and Oct-1) and IL-2E (which binds NF-AT), and completely substitutes for the Ca2+ co-stimulus required to stimulate an NF-kappa B-dependent element. Calcineurin stimulates the NF-kappa B element by enhancing inactivation of I kappa B/MAD3, an inhibitor of NF-kappa B, thereby increasing the amount of nuclear NF-kappa B DNA binding activity. These data provide the first demonstration in vivo that activation of a protein phosphatase can inactivate I kappa B, and suggest one possible explanation for mechanism-based toxicities associated with FK-506 and CsA by demonstrating that these drugs can inhibit the calcineurin-dependent activation of a virtually ubiquitous transcription factor. |
| Databáze: | OpenAIRE |
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