MSK regulate TCR-induced CREB phosphorylation but not immediate early gene transcription
MSK regulate TCR-induced CREB phosphorylation but not immediate early gene transcription
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DOI：
10.1002/eji.200636606
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发表时间：
2007-09-01
影响因子：
5.4
通讯作者：
Macdonald, Andrew
中科院分区：
文献类型：
--
作者：
Kaiser, Madlen;Wiggin, Giselle R.;Macdonald, Andrew
刺激T细胞受体激活ERK1/2和p38丝裂原活化蛋白激酶(MAPK)级联反应。我们证明，TCR刺激也激活了丝裂原激活和应激激活的激酶(MSK)。在T细胞系和原代外周T细胞中均位于ERK1/2和p38下游。MSK1/2基因敲除小鼠胸腺中的T细胞数量正常，这些细胞的发育似乎没有受到影响。利用MSK1/2基因敲除小鼠的原始T细胞和T淋巴母细胞，发现MSK是负责转录因子CREB在TCR刺激下磷酸化的激酶。在不同类型的细胞中，MSK对CREB的磷酸化与MAPK信号下游的Nur77、Nor1和c-fos的转录有关。在T细胞中，这些基因的TCR依赖的转录被发现需要依赖于MAPK但不依赖MSK的信号通路。然而，与野生型小鼠相比，MSK1/2基因敲除小鼠的脾中存在的T细胞数量以及IL-2诱导的这些细胞的增殖减少。这与TCR诱导的IL-2受体CD25上调的减少以及在IL-2诱导的CREB磷酸化中需要MSK有关。
Stimulation of the T cell receptor activates the ERK1/2 and p38 mitogen-activated protein kinase (MAPK) cascades. We demonstrate that TCR stimulation also activates the mitogen- and stress-activated kinases (MSK). downstream of ERK1/2 and p38 in both a T cell line and primary peripheral T cells. MSK1/2-knockout mice were found to have normal numbers of T cells in the thymus, and development of these cells appeared unaffected. Using naive T cells and T lymphoblasts from MSK1/2-knockout mice, it was found that MSK was the kinase responsible for phosphorylation of the transcription factor CREB in response to TCR stimulation. Phosphorylation of CREB by MSK has been linked to the transcription of nur77, nor1 and c-fos downstream of MAPK signalling in various cell types. In T cells, the TCR-dependent transcription of these genes was found to require a MAPK-dependent but MSK-independent signalling pathway. Nevertheless, the number of T cells present in the spleens of MSK1/2-knockout mice and the IL-2-induced proliferation of these cells was reduced compared to wild-type mice. This correlated to a reduction in the TCR-induced up-regulation of the IL-2 receptor CD25 and a requirement for MSK in IL-2-induced CREB phosphorylation.