Deletion of calcineurin and myocyte enhancer factor 2 (MEF2) binding domain of Cabin1 results in enhanced cytokine gene expression in T cells.
Deletion of calcineurin and myocyte enhancer factor 2 (MEF2) binding domain of Cabin1 results in enhanced cytokine gene expression in T cells.
复制标题
钙调蛋白和肌细胞增强子因子2（MEF2）结合结构域的缺失导致T细胞中的细胞因子基因表达增强。
DOI：
10.1084/jem.194.10.1449
复制
发表时间：
2001-11-19
影响因子：
15.3
通讯作者：
Chen, J
中科院分区：
文献类型：
--
作者：
Esau, C;Boes, M;Youn, H D;Tatterson, L;Liu, J O;Chen, J
Cabin 1通过其COOH末端区域结合钙调磷酸酶和肌细胞增强因子2（MEF 2）。在细胞系中，这些相互作用显示出在T细胞受体（TCR）信号传导和MEF 2对Nur 77的转录激活后抑制钙调磷酸酶活性。这些相互作用在生理条件下的作用进行了研究，使用突变的小鼠品系，表达一个截短的Cabin 1缺乏COOH-末端钙调磷酸酶和MEF 2结合结构域。突变小鼠T、B细胞发育及胸腺细胞凋亡正常。然而，在对抗CD 3刺激的反应中，突变T细胞表达的白细胞介素（IL）-2，IL-4，IL-9，IL-13和干扰素γ水平显著高于野生型T细胞。增强的细胞因子基因表达与活化T细胞核因子（NF-AT）c或NF-ATp核转位的变化无关，但在突变T细胞中诱导磷酸化形式的MEF 2D之前。与增强的细胞因子表达一致，突变小鼠血清免疫球蛋白（IG）G1、IgG 2b和IgE水平升高，并产生更多的IgG 1以响应T细胞依赖性抗原。这些发现表明，钙调神经磷酸酶和MEF 2的Cabin 1结合域是胸腺细胞发育和凋亡的关键，但需要适当的调节T细胞细胞因子的表达可能通过调节MEF 2的活性。
Cabin1 binds calcineurin and myocyte enhancer factor 2 (MEF2) through its COOH-terminal region. In cell lines, these interactions were shown to inhibit calcineurin activity after T cell receptor (TCR) signaling and transcriptional activation of Nur77 by MEF2. The role of these interactions under physiological conditions was investigated using a mutant mouse strain that expresses a truncated Cabin1 lacking the COOH-terminal calcineurin and MEF2 binding domains. T and B cell development and thymocyte apoptosis were normal in mutant mice. In response to anti-CD3 stimulation, however, mutant T cells expressed significantly higher levels of interleukin (IL)-2, IL-4, IL-9, IL-13, and interferon γ than wild-type T cells. The enhanced cytokine gene expression was not associated with change in nuclear factor of activated T cells (NF-AT)c or NF-ATp nuclear translocation but was preceded by the induction of a phosphorylated form of MEF2D in mutant T cells. Consistent with the enhanced cytokine expression, mutant mice had elevated levels of serum immunoglobulin (Ig)G1, IgG2b, and IgE and produced more IgG1 in response to a T cell–dependent antigen. These findings suggest that the calcineurin and MEF2 binding domain of Cabin1 is dispensable for thymocyte development and apoptosis, but is required for proper regulation of T cell cytokine expression probably through modulation of MEF2 activity.