Cot kinase induces cyclooxygenase-2 expression in T cells through activation of the nuclear factor of activated T cells.
Cyclooxygenase-2 (COX-2) is induced in human T lymphocytes upon T cell receptor triggering. Here we report that Cot kinase, a mitogen-activated protein kinase kinase kinase involved in T cell activation, up-regulates COX-2 gene expression in Jurkat T cells. Induction of COX-2 promoter activity by Cot kinase occurred mainly through activation of the nuclear factor of activated T cells (NFAT). Mutation of the distal (-105/-97) and proximal (-76/-61) NFAT response elements in the COX-2 promoter abolished the activation induced by Cot kinase. Even more, coexpression of a dominant negative version of NFAT inhibited Cot kinase-mediated COX-2 promoter activation, whereas cotransfection of a constitutively active version of the calcium-dependent phosphatase calcineurin synergizes with Cot kinase in the up-regulation of COX-2 promoter-driven transcription. Strikingly, Cot kinase increased transactivation mediated by a GAL4-NFAT fusion protein containing the N-terminal transactivation domain of NFATp. In contrast to phorbol ester plus calcium ionophore A23187, Cot kinase increases both COX-2 promoter activity and NFAT-mediated transactivation in a cyclosporin A-independent manner. These data indicate that Cot kinase up-regulates COX-2 promoter-driven transcription through the NFAT response elements, being the Cot kinase-induced NFAT-dependent transactivation presumably implicated in this up-regulation.
de Gregorio
R
R
Instituto de Investigaciónes Biomédicas, Consejo Superior de Investigaciónes Cientificas (CSIC), Facultad Medicina, Universidad Autónoma de Madrid (UAM), Spain.
Iñiguez
M A
MA
Fresno
M
M
Alemany
S
S
D001483:Base Sequence; D019703:Calcineurin / Q000378:metabolism; D051546:Cyclooxygenase 2; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics*; D019169:Jurkat Cells; D020930:MAP Kinase Kinase Kinases / Q000502:physiology*; D008565:Membrane Proteins; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D013601:T-Lymphocytes / Q000201:enzymology*; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation; D015854:Up-Regulation / Q000502:physiology
D017931:DNA Primers; D004268:DNA-Binding Proteins; D007527:Isoenzymes; D008565:Membrane Proteins; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D020930:MAP Kinase Kinase Kinases; C069937:MAP3K8 protein, human; D019703:Calcineurin