Cot kinase induces cyclooxygenase-2 expression in T cells through activation of the nuclear factor of activated T cells
Cot kinase induces cyclooxygenase-2 expression in T cells through activation of the nuclear factor of activated T cells
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DOI：
10.1074/jbc.m100885200
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发表时间：
2001-07-20
影响因子：
4.8
通讯作者：
Alemany, S
中科院分区：
文献类型：
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作者：
de Gregorio, R;Iñiguez, MA;Alemany, S
环氧合酶-2(COX-2)是在T细胞受体激活后在人T淋巴细胞中诱导产生的。在这里，我们报道了Cot激酶，一种参与T细胞激活的丝裂原激活的蛋白激酶，上调Jurkat T细胞中COX-2基因的表达。Cot激酶诱导COX-2启动子活性主要是通过激活活化T细胞核因子(NFAT)实现的。COX-2启动子远端(-105/-97)和近端(-76/-61)整齐反应元件的突变可消除Cot激酶诱导的激活。此外，共表达显性阴性版本的NFAT抑制了Cot激酶介导的COX-2启动子的激活，而共转染钙依赖磷酸酶钙调神经磷酸酶与Cot激酶协同上调了COX-2启动子驱动的转录。值得注意的是，Cot激酶增加了GAL4-NFAT融合蛋白介导的反式激活，该融合蛋白包含NFATp的N端反式激活结构域。与佛波酯+钙离子载体A23187不同，Cot激酶以环孢素A不依赖的方式增加COX-2启动子活性和NFAT介导的反式激活。这些数据表明，Cot激酶通过NFAT反应元件上调COX-2启动子驱动的转录，这可能是Cot激酶诱导的NFAT依赖的反式激活。
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) NEAT 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.