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dc.contributor.authorMulero, M. Carmen-
dc.contributor.authorAubareda, Anna-
dc.contributor.authorOrzáez, Mar-
dc.contributor.authorMesseguer, Joaquim-
dc.contributor.authorSerrano-Candelas, Eva-
dc.contributor.authorMartínez-Hoyer, Sergio-
dc.contributor.authorMesseguer Peypoch, Ángel-
dc.contributor.authorPérez-Payá, Enrique-
dc.contributor.authorPérez-Riba, Mercè-
dc.date.accessioned2010-07-02T08:13:02Z-
dc.date.available2010-07-02T08:13:02Z-
dc.date.issued2009-04-03-
dc.identifier.citationJournal of Biological Chemistry 284(14): 9394-9401 (2009)en_US
dc.identifier.issn0021-9258-
dc.identifier.urihttp://hdl.handle.net/10261/25904-
dc.description8 pages, 5 figures.-- PMID: 19189965 [PubMed].-- PMCID: PMC2666591.-- Supplementary information available at: http://www.jbc.org/content/suppl/2009/02/05/M805889200.DC1.htmlen_US
dc.description.abstractCalcineurin phosphatase plays a crucial role in T cell activation. Dephosphorylation of the nuclear factors of activated T cells (NFATs) by calcineurin is essential for activating cytokine gene expression and, consequently, the immune response. Current immunosuppressive protocols are based mainly on calcineurin inhibitors, cyclosporine A and FK506. Unfortunately, these drugs are associated with severe side effects. Therefore, immunosuppressive agents with higher selectivity and lower toxicity must be identified. The immunosuppressive role of the family of proteins regulators of calcineurin (RCAN, formerly known as DSCR1) which regulate the calcineurin-NFAT signaling pathway, has been described recently. Here, we identify and characterize the minimal RCAN sequence responsible for the inhibition of calcineurin-NFAT signaling in vivo. The RCAN-derived peptide spanning this sequence binds to calcineurin with high affinity. This interaction is competed by a peptide spanning the NFAT PXIXIT sequence, which binds to calcineurin and facilitates NFAT dephosphorylation and activation. Interestingly, the RCAN-derived peptide does not inhibit general calcineurin phosphatase activity, which suggests that it may have a specific immunosuppressive effect on the calcineurin-NFAT signaling pathway. As such, the RCAN-derived peptide could either be considered a highly selective immunosuppressive compound by itself or be used as a new tool for identifying innovative immunosuppressive agents. We developed a low throughput assay, based on the RCAN1-calcineurin interaction, which identifies dipyridamole as an efficient in vivo inhibitor of the calcineurin-NFAT pathway that does not affect calcineurin phosphatase activity.en_US
dc.description.sponsorshipThis work was supported by grants from the Fundació La Marató de TV3 (Reference 030830), the Generalitat de Catalunya (Reference 2006 BE 00051), the Spanish Ministry of Education and Science (Grants SAF2006-04815, BIO2004-00998, BIO2007-60066, CTQ2005-00995/BQU), and the Fundación Mutua Madrileña 2007. The costs of publication of this article were defrayed in part by the payment of page charges.en_US
dc.format.extent641708 bytes-
dc.format.mimetypeapplication/pdf-
dc.language.isoengen_US
dc.publisherAmerican Society for Biochemistry and Molecular Biologyen_US
dc.relation.isversionofPublisher's version-
dc.rightsopenAccessen_US
dc.titleInhibiting the calcineurin-NFAT (nuclear factor of activated T cells) signaling pathway with a regulator of calcineurin-derived peptide without affecting general calcineurin phosphatase activityen_US
dc.typeartículoen_US
dc.identifier.doi10.1074/jbc.M805889200-
dc.description.peerreviewedPeer revieweden_US
dc.relation.publisherversionhttp://dx.doi.org/10.1074/jbc.M805889200en_US
dc.identifier.e-issn1083-351X-
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