Whitehurst C E, Geppert T D
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas 73535, USA.
J Immunol. 1996 Feb 1;156(3):1020-9.
TCR engagement stimulates the activation of the protein kinase Raf-1. Active Raf-1 phosphorylates and activates the mitogen-activated protein (MAP) kinase/extracellular signal-regulated kinase kinase 1 (MEK1), which in turn phosphorylates and activates the MAP kinases/extracellular signal regulated kinases, ERK1 and ERK2. Raf-1 activity promotes IL-2 production in activated T lymphocytes. Therefore, we sought to determine whether MEK1 and ERK activities also stimulate IL-2 gene transcription. Expression of constitutively active Raf-1 or MEK1 in Jurkat T cells enhanced the stimulation of IL-2 promoter-driven transcription stimulated by a calcium ionophore and PMA, and together with a calcium ionophore the expression of each protein was sufficient to stimulate NF-AT activity. Expression of MEK1-interfering mutants inhibited the stimulation of IL-2 promoter-driven transcription and blocked the ability of constitutively active Ras and Raf-1 to costimulate NF-AT activity with a calcium ionophore. Expression of the MAP kinase-specific phosphatase, MKP-1, which blocks ERK activation, inhibited IL-2 promoter and NF-AT-driven transcription stimulated by a calcium ionophore and PMA, and in addition, MKP-1 neutralized the transcriptional enhancement caused by active Raf-1 and MEK1 expression. We conclude that the MAP kinase signal transduction pathway consisting of Raf-1, MEK1, and ERK1 and ERK2 functions in the stimulation IL-2 gene transcription in activated T lymphocytes.
TCR的结合刺激蛋白激酶Raf-1的激活。活性Raf-1磷酸化并激活丝裂原活化蛋白（MAP）激酶/细胞外信号调节激酶激酶1（MEK1），MEK1进而磷酸化并激活MAP激酶/细胞外信号调节激酶ERK1和ERK2。Raf-1活性促进活化的T淋巴细胞中IL-2的产生。因此，我们试图确定MEK1和ERK活性是否也刺激IL-2基因转录。在Jurkat T细胞中组成型活性Raf-1或MEK1的表达增强了钙离子载体和PMA刺激的IL-2启动子驱动的转录，并且与钙离子载体一起，每种蛋白的表达足以刺激NF-AT活性。MEK1干扰突变体的表达抑制了IL-2启动子驱动的转录刺激，并阻断了组成型活性Ras和Raf-1与钙离子载体共刺激NF-AT活性的能力。阻断ERK激活的MAP激酶特异性磷酸酶MKP-1的表达抑制了钙离子载体和PMA刺激的IL-2启动子和NF-AT驱动的转录，此外，MKP-1中和了由活性Raf-1和MEK1表达引起的转录增强。我们得出结论，由Raf-1、MEK1以及ERK1和ERK2组成的MAP激酶信号转导途径在活化的T淋巴细胞中刺激IL-2基因转录中起作用。
