Activation of Nuclear Factor of Activated T Cells in a Cyclosporin A-resistant Pathway (∗)
The mechanism of action of the immunosuppressive drug cyclosporin A (CsA) is the inactivation of the Ca2+/calmodulin-dependent serine-threonine phosphatase calcineurin by the drug-immunophilin complex. Inactive calcineurin is unable to activate the nuclear factor of activated T cells (NFAT), a trans...
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Veröffentlicht in: | The Journal of biological chemistry 1996-03, Vol.271 (13), p.7700-7704 |
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creator | Ghosh, Paritosh Sica, Antonio Cippitelli, Marco Subleski, Jeff Lahesmaa, Riitta Young, Howard A. Rice, Nancy R. |
description | The mechanism of action of the immunosuppressive drug cyclosporin A (CsA) is the inactivation of the Ca2+/calmodulin-dependent serine-threonine phosphatase calcineurin by the drug-immunophilin complex. Inactive calcineurin is unable to activate the nuclear factor of activated T cells (NFAT), a transcription factor required for expression of the interleukin 2 (IL-2) gene. IL-2 production by CsA-treated cells is therefore dramatically reduced. We demonstrate here, however, that NFAT can be activated, and significant levels of IL-2 can be produced by the CsA-resistant CD28-signaling pathway. In transient transfection assays, both multicopy NFAT- and IL-2 promoter-β-galactosidase reporter gene constructs could be activated by phorbol 12-myristate 13-acetate (PMA)/αCD28 stimulation, and this activation was resistant to CsA. Electrophoretic mobility shift assay showed the induction of a CsA-resistant NFAT complex in the nuclear extracts of peripheral blood T cells stimulated with PMA plus αCD28. Peripheral blood T cells stimulated with PMA/αCD28 produced IL-2 in the presence of CsA. Collectively, these data suggest that NFAT can be activated and IL-2 can be produced in a calcineurin independent manner. |
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Inactive calcineurin is unable to activate the nuclear factor of activated T cells (NFAT), a transcription factor required for expression of the interleukin 2 (IL-2) gene. IL-2 production by CsA-treated cells is therefore dramatically reduced. We demonstrate here, however, that NFAT can be activated, and significant levels of IL-2 can be produced by the CsA-resistant CD28-signaling pathway. In transient transfection assays, both multicopy NFAT- and IL-2 promoter-β-galactosidase reporter gene constructs could be activated by phorbol 12-myristate 13-acetate (PMA)/αCD28 stimulation, and this activation was resistant to CsA. Electrophoretic mobility shift assay showed the induction of a CsA-resistant NFAT complex in the nuclear extracts of peripheral blood T cells stimulated with PMA plus αCD28. Peripheral blood T cells stimulated with PMA/αCD28 produced IL-2 in the presence of CsA. Collectively, these data suggest that NFAT can be activated and IL-2 can be produced in a calcineurin independent manner.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.271.13.7700</identifier><identifier>PMID: 8631809</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Base Sequence ; Cells, Cultured ; Cyclosporine - pharmacology ; DNA-Binding Proteins - biosynthesis ; DNA-Binding Proteins - metabolism ; Drug Resistance ; Humans ; Interleukin-2 - biosynthesis ; Interleukin-2 - genetics ; Molecular Sequence Data ; NFATC Transcription Factors ; Nuclear Proteins - biosynthesis ; Nuclear Proteins - metabolism ; Oligodeoxyribonucleotides ; Plasmids ; Promoter Regions, Genetic ; Recombinant Fusion Proteins - biosynthesis ; Recombinant Fusion Proteins - metabolism ; T-Lymphocytes - drug effects ; T-Lymphocytes - immunology ; T-Lymphocytes - metabolism ; Transcription Factors - biosynthesis ; Transcription Factors - metabolism</subject><ispartof>The Journal of biological chemistry, 1996-03, Vol.271 (13), p.7700-7704</ispartof><rights>1996 © 1996 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c442t-f9316f50d8fe7723128a40b60140fa544debdd0d6aca59395b3de1ffe3dafe353</citedby><cites>FETCH-LOGICAL-c442t-f9316f50d8fe7723128a40b60140fa544debdd0d6aca59395b3de1ffe3dafe353</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/8631809$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ghosh, Paritosh</creatorcontrib><creatorcontrib>Sica, Antonio</creatorcontrib><creatorcontrib>Cippitelli, Marco</creatorcontrib><creatorcontrib>Subleski, Jeff</creatorcontrib><creatorcontrib>Lahesmaa, Riitta</creatorcontrib><creatorcontrib>Young, Howard A.</creatorcontrib><creatorcontrib>Rice, Nancy R.</creatorcontrib><title>Activation of Nuclear Factor of Activated T Cells in a Cyclosporin A-resistant Pathway (∗)</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>The mechanism of action of the immunosuppressive drug cyclosporin A (CsA) is the inactivation of the Ca2+/calmodulin-dependent serine-threonine phosphatase calcineurin by the drug-immunophilin complex. Inactive calcineurin is unable to activate the nuclear factor of activated T cells (NFAT), a transcription factor required for expression of the interleukin 2 (IL-2) gene. IL-2 production by CsA-treated cells is therefore dramatically reduced. We demonstrate here, however, that NFAT can be activated, and significant levels of IL-2 can be produced by the CsA-resistant CD28-signaling pathway. In transient transfection assays, both multicopy NFAT- and IL-2 promoter-β-galactosidase reporter gene constructs could be activated by phorbol 12-myristate 13-acetate (PMA)/αCD28 stimulation, and this activation was resistant to CsA. Electrophoretic mobility shift assay showed the induction of a CsA-resistant NFAT complex in the nuclear extracts of peripheral blood T cells stimulated with PMA plus αCD28. Peripheral blood T cells stimulated with PMA/αCD28 produced IL-2 in the presence of CsA. Collectively, these data suggest that NFAT can be activated and IL-2 can be produced in a calcineurin independent manner.</description><subject>Base Sequence</subject><subject>Cells, Cultured</subject><subject>Cyclosporine - pharmacology</subject><subject>DNA-Binding Proteins - biosynthesis</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Drug Resistance</subject><subject>Humans</subject><subject>Interleukin-2 - biosynthesis</subject><subject>Interleukin-2 - genetics</subject><subject>Molecular Sequence Data</subject><subject>NFATC Transcription Factors</subject><subject>Nuclear Proteins - biosynthesis</subject><subject>Nuclear Proteins - metabolism</subject><subject>Oligodeoxyribonucleotides</subject><subject>Plasmids</subject><subject>Promoter Regions, Genetic</subject><subject>Recombinant Fusion Proteins - biosynthesis</subject><subject>Recombinant Fusion Proteins - metabolism</subject><subject>T-Lymphocytes - drug effects</subject><subject>T-Lymphocytes - immunology</subject><subject>T-Lymphocytes - metabolism</subject><subject>Transcription Factors - biosynthesis</subject><subject>Transcription Factors - metabolism</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1996</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkMGKFDEQhoMo67h69iQEhEUPPVvpdHc6x2FwVVhWDyt4EEI6qThZejpjktll3sA32PfbJzHDDB4E2TqkqPx__RQfIa8ZzBmI5vxmMPNasDnjcyEAnpAZg55XvGXfn5IZQM0qWbf9c_IipRso1Uh2Qk76jrMe5Iz8WJjsb3X2YaLB0autGVFHeqFNDnH_c9TR0mu6xHFM1E9U0-XOjCFtQizTooqYfMp6yvSrzqs7vaPvHn7fv39Jnjk9Jnx17Kfk28WH6-Wn6vLLx8_LxWVlmqbOlZOcda4F2zsUouas7nUDQwesAafbprE4WAu200a3kst24BaZc8itLk_LT8nZIXcTw68tpqzWPplyrJ4wbJMSPTAJJfkxIxPAO9mJYjw_GE0MKUV0ahP9WsedYqD24FUBrwp4xbjagy8bb47R22GN9q__SLrobw_6yv9c3fmIavDBrHD9T4o8uLDguvUYVTIeJ4O2bJisbPD_veAPsR2drQ</recordid><startdate>19960329</startdate><enddate>19960329</enddate><creator>Ghosh, Paritosh</creator><creator>Sica, Antonio</creator><creator>Cippitelli, Marco</creator><creator>Subleski, Jeff</creator><creator>Lahesmaa, Riitta</creator><creator>Young, Howard A.</creator><creator>Rice, Nancy R.</creator><general>Elsevier Inc</general><general>American Society for Biochemistry and Molecular Biology</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7T5</scope><scope>7TM</scope><scope>H94</scope><scope>7X8</scope></search><sort><creationdate>19960329</creationdate><title>Activation of Nuclear Factor of Activated T Cells in a Cyclosporin A-resistant Pathway (∗)</title><author>Ghosh, Paritosh ; Sica, Antonio ; Cippitelli, Marco ; Subleski, Jeff ; Lahesmaa, Riitta ; Young, Howard A. ; Rice, Nancy R.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c442t-f9316f50d8fe7723128a40b60140fa544debdd0d6aca59395b3de1ffe3dafe353</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1996</creationdate><topic>Base Sequence</topic><topic>Cells, Cultured</topic><topic>Cyclosporine - pharmacology</topic><topic>DNA-Binding Proteins - biosynthesis</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>Drug Resistance</topic><topic>Humans</topic><topic>Interleukin-2 - biosynthesis</topic><topic>Interleukin-2 - genetics</topic><topic>Molecular Sequence Data</topic><topic>NFATC Transcription Factors</topic><topic>Nuclear Proteins - biosynthesis</topic><topic>Nuclear Proteins - metabolism</topic><topic>Oligodeoxyribonucleotides</topic><topic>Plasmids</topic><topic>Promoter Regions, Genetic</topic><topic>Recombinant Fusion Proteins - biosynthesis</topic><topic>Recombinant Fusion Proteins - metabolism</topic><topic>T-Lymphocytes - drug effects</topic><topic>T-Lymphocytes - immunology</topic><topic>T-Lymphocytes - metabolism</topic><topic>Transcription Factors - biosynthesis</topic><topic>Transcription Factors - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ghosh, Paritosh</creatorcontrib><creatorcontrib>Sica, Antonio</creatorcontrib><creatorcontrib>Cippitelli, Marco</creatorcontrib><creatorcontrib>Subleski, Jeff</creatorcontrib><creatorcontrib>Lahesmaa, Riitta</creatorcontrib><creatorcontrib>Young, Howard A.</creatorcontrib><creatorcontrib>Rice, Nancy R.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ghosh, Paritosh</au><au>Sica, Antonio</au><au>Cippitelli, Marco</au><au>Subleski, Jeff</au><au>Lahesmaa, Riitta</au><au>Young, Howard A.</au><au>Rice, Nancy R.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Activation of Nuclear Factor of Activated T Cells in a Cyclosporin A-resistant Pathway (∗)</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>1996-03-29</date><risdate>1996</risdate><volume>271</volume><issue>13</issue><spage>7700</spage><epage>7704</epage><pages>7700-7704</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>The mechanism of action of the immunosuppressive drug cyclosporin A (CsA) is the inactivation of the Ca2+/calmodulin-dependent serine-threonine phosphatase calcineurin by the drug-immunophilin complex. Inactive calcineurin is unable to activate the nuclear factor of activated T cells (NFAT), a transcription factor required for expression of the interleukin 2 (IL-2) gene. IL-2 production by CsA-treated cells is therefore dramatically reduced. We demonstrate here, however, that NFAT can be activated, and significant levels of IL-2 can be produced by the CsA-resistant CD28-signaling pathway. In transient transfection assays, both multicopy NFAT- and IL-2 promoter-β-galactosidase reporter gene constructs could be activated by phorbol 12-myristate 13-acetate (PMA)/αCD28 stimulation, and this activation was resistant to CsA. Electrophoretic mobility shift assay showed the induction of a CsA-resistant NFAT complex in the nuclear extracts of peripheral blood T cells stimulated with PMA plus αCD28. Peripheral blood T cells stimulated with PMA/αCD28 produced IL-2 in the presence of CsA. 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subjects | Base Sequence Cells, Cultured Cyclosporine - pharmacology DNA-Binding Proteins - biosynthesis DNA-Binding Proteins - metabolism Drug Resistance Humans Interleukin-2 - biosynthesis Interleukin-2 - genetics Molecular Sequence Data NFATC Transcription Factors Nuclear Proteins - biosynthesis Nuclear Proteins - metabolism Oligodeoxyribonucleotides Plasmids Promoter Regions, Genetic Recombinant Fusion Proteins - biosynthesis Recombinant Fusion Proteins - metabolism T-Lymphocytes - drug effects T-Lymphocytes - immunology T-Lymphocytes - metabolism Transcription Factors - biosynthesis Transcription Factors - metabolism |
title | Activation of Nuclear Factor of Activated T Cells in a Cyclosporin A-resistant Pathway (∗) |
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