BCL11B enhances TCR/CD28-triggered NF-κB activation through up-regulation of Cot kinase gene expression in T-lymphocytes

BCL11B is a Transcriptional regulator with all important role in T-cell development and leukaemogenesis. We demonstrated recently that BCL11B controls expression from the IL (interleukin)-2 promoter through direct binding to file USI (upstream site 1). fit the present study, we provide evidence that BCL11B also participates in the activation of IL-2 gene expression by enhancing NF-kappa B (nuclear factor kappa B) activity in the context of TCR (T-cell receptor)/CD28-triggered T-cell activation. Enhanced NF-kappa B activation is not a consequence of BCL11B binding to file NF-kappa B response elements or association with the NF-kappa B-DNA complexes, but rather the result of higher translocation of NF-kappa B to the nucleus Caused by enhanced degradation Of I kappa B (inhibitor of NF-kappa B). The enhanced I kappa B degradation in cells with increased levels of BCL11B wits specific for T-cells activated through the TCR, but not for cells activated through TNF alpha (tumour necrosis factor alpha) or UV light, and was caused by increased activity of I kappa B kinase, as indicated by its increase in phosphorylation. As BCL11B is a transcription factor, we investigated whether the expression of genes upstream of I kappa B kinase in the TCR/CD28 signalling pathway was affected by increased BCL11B expression, and found that Cot (cancer Osaka thyroid oncogene) kinase mRNA levels were elevated. Cot kinase is known to promote enhanced I kappa B kinase activity, which results in the phosphorylation and degradation Of I kappa B and activation of NF-kappa B. The implied involvement of Cot kinase in BCL11B-mediated NF-kappa B activation in response to TCR activation is supported by the fact that a Cot kinase dominant-negative mutant or Cot kinase siRNA (small interfering RNA) knockdown blocked BCL11B mediated NF-kappa B activation. In support Of Our observations, in the present study we report that BCL11B enhances the expression of several other NF-kappa B Target genes, in addition to IL-2. fit addition, we provide evidence that BCL11B associates with intron 2 of the Cot kinase gene to regulate its expression.