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Wolverhampton Intellectual Repository and E-Theses > Research Institutes > Research Institute in Healthcare Science > Molecular Pharmacology Research Group > Blockade of T-cell activation by dithiocarbamates involves novel mechanisms of inhibition of nuclear factor of activated T cells.

Please use this identifier to cite or link to this item: http://hdl.handle.net/2436/7738
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Title: Blockade of T-cell activation by dithiocarbamates involves novel mechanisms of inhibition of nuclear factor of activated T cells.
Authors: Martínez-Martínez, Sara
Gómez del Arco, Pablo
Armesilla, Angel Luis
Aramburu, Jose
Luo, Chun
Rao, Anjana
Redondo, Juan Miguel
Citation: Molecular and Cellular Biology, 17(11): 6437-6447
Publisher: American Society for Microbiology
Issue Date: 1997
URI: http://hdl.handle.net/2436/7738
PubMed ID: 9343406
Additional Links: http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=232496&blobtype=pdf
http://direct.bl.uk/bld/PlaceOrder.do?UIN=034301189&ETOC=RN&from=searchengine
http://mcb.asm.org/cgi/content/abstract/17/11/6437
Abstract: Dithiocarbamates (DTCs) have recently been reported as powerful inhibitors of NF-kappaB activation in a number of cell types. Given the role of this transcription factor in the regulation of gene expression in the inflammatory response, NF-kappaB inhibitors have been suggested as potential therapeutic drugs for inflammatory diseases. We show here that DTCs inhibited both interleukin 2 (IL-2) synthesis and membrane expression of antigens which are induced during T-cell activation. This inhibition, which occurred with a parallel activation of c-Jun transactivating functions and expression, was reflected by transfection experiments at the IL-2 promoter level, and involved not only the inhibition of NF-kappaB-driven reporter activation but also that of nuclear factor of activated T cells (NFAT). Accordingly, electrophoretic mobility shift assays (EMSAs) indicated that pyrrolidine DTC (PDTC) prevented NF-kappaB, and NFAT DNA-binding activity in T cells stimulated with either phorbol myristate acetate plus ionophore or antibodies against the CD3-T-cell receptor complex and simultaneously activated the binding of AP-1. Furthermore, PDTC differentially targeted both NFATp and NFATc family members, inhibiting the transactivation functions of NFATp and mRNA induction of NFATc. Strikingly, Western blotting and immunocytochemical experiments indicated that PDTC promoted a transient and rapid shuttling of NFATp and NFATc, leading to their accelerated export from the nucleus of activated T cells. We propose that the activation of an NFAT kinase by PDTC could be responsible for the rapid shuttling of the NFAT, therefore transiently converting the sustained transactivation of this transcription factor that occurs during lymphocyte activation, and show that c-Jun NH2-terminal kinase (JNK) can act by directly phosphorylating NFATp. In addition, the combined inhibitory effects on NFAT and NF-KB support a potential use of DTCs as immunosuppressants.
Type: Article
Language: en
Keywords: Dithiocarbamates
Transcription factor
DTCs
T-cell activation
ISSN: 0270-7306
Appears in Collections: Molecular Pharmacology Research Group

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