BCL11B enhances TCR/CD28-triggered NF-kappaB activation through up-regulation of Cot kinase gene expression in T-lymphocytes.
BCL11B enhances TCR/CD28-triggered NF-kappaB activation through up-regulation of Cot kinase gene expression in T-lymphocytes.
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DOI：
10.1042/bj20080925
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发表时间：
2009-01-15
期刊：
影响因子：
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通讯作者：
Avram D
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文献类型：
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作者：
Cismasiu VB;Duque J;Paskaleva E;Califano D;Ghanta S;Young HA;Avram D
BCL11B是一种转录调节因子，在T细胞发育和白血病发生中起重要作用。最近，我们证明BCL11B通过直接结合US1位点控制IL-2启动子的表达。本研究提供的证据表明，在TCR/ cd28触发T细胞活化的情况下，BCL11B也通过增强NF-kB活性参与IL-2基因表达的活化。NF-kB活化增强不是BCL11B与NF-kB应答元件结合或与NF-kB- dna复合物结合的结果，而是IkB降解增强导致NF-kB向细胞核转移的结果。在BCL11B水平升高的细胞中，IkB降解的增强是通过TCR激活的T细胞所特有的，而不是通过TNFα或UV激活的，并且是由更高的IkB激酶活性引起的，正如其更高的磷酸化所表明的那样。由于BCL11B是一种转录因子，我们研究了TCR/CD28信号通路中IkB激酶上游基因的表达是否受到BCL11B表达增加的影响，发现Cot激酶mRNA水平升高。已知Cot激酶可促进IkB激酶活性增强，从而导致IkB抑制剂的磷酸化和降解以及NF-kB的激活。Cot激酶在bcl11b介导的NF-kB激活中对TCR激活的影响得到了Cot激酶显性负突变体或Cot激酶siRNA阻断bcl11b介导的NF-kB激活的事实的支持。为了支持我们的观察结果，我们报告BCL11B增强了其他几种NF-kB靶基因的表达，除了IL-2。此外，我们提供的证据表明，BCL11B与Cot激酶基因内含子2结合，调节其表达。
BCL11B is a transcriptional regulator with important role in T cell development and leukemogenesis. Recently we demonstrated that BCL11B controls expression from IL-2 promoter through direct binding to the US1 site. Here we provide evidence that BCL11B also participates in the activation of IL-2 gene expression by enhancing NF-kB activity in the context of TCR/CD28–triggered T cell activation. Enhanced NF-kB activation is not a consequence of BCL11B binding to the NF-kB response elements or association with the NF-kB-DNA complexes, but rather the result of higher translocation of NF-kB to the nucleus caused by enhanced degradation of the IkB. The enhanced IkB degradation in cells with increased levels of BCL11B was specific for T cells activated through TCR, but not through TNFα or UV, and was caused by higher activity of IkB kinase, as indicated by its higher phosphorylation. As BCL11B is a transcription factor we investigated whether expression of genes upstream of IkB kinase in the TCR/CD28 signaling pathway was affected by increased BCL11B expression, and found that Cot kinase mRNA levels were elevated. Cot kinase is known to promote enhanced IkB kinase activity which results in phosphorylation and degradation of the IkB inhibitors and activation of NF-kB. Implication of Cot kinase in BCL11B-mediated NF-kB activation in response TCR activation is supported by the fact that a Cot kinase dominant negative mutant or Cot kinase siRNA blocked BCL11B-mediated NF-kB activation. In support of our observations, we report that BCL11B enhances expression of several other NF-kB target genes, in addition to IL-2. In addition, we provide evidence that BCL11B associates with Cot kinase gene intron 2 to regulate its expression.