JunD/AP-1 and STAT3 are the major enhancer molecules for high Bcl6 expression in germinal center B cells
JunD/AP-1 and STAT3 are the major enhancer molecules for high Bcl6 expression in germinal center B cells
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DOI：
10.1093/intimm/dxl041
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发表时间：
2006-07-01
影响因子：
4.4
通讯作者：
Tokuhisa, Takeshi
中科院分区：
文献类型：
--
作者：
Arguni, Eggi;Arima, Masafumi;Tokuhisa, Takeshi
Bcl 6原癌基因编码转录阻遏物，广泛表达且主要在生殖中心（GC）B细胞中。虽然已经报道了人Bcl 6基因的启动子区域，但是其在GC B细胞中高表达的增强子分子在很大程度上是未知的。在这里，我们表明小鼠Bcl 6基因的转录起始位点与报道的人类基因不同。新启动子区域周围的DNA序列在小鼠和人类之间高度保守，并且没有典型的TATA或CCAAT盒。启动子区的两个AP-1结合元件是GC来源的B淋巴瘤细胞中的主要增强子元件，并且在GC B细胞中检测到JunD/AP-1。此外，我们确定了沉默区与三个Bcl 6结合元件周围的起始位点。Bcl 6与沉默元件结合，其过表达通过沉默元件抑制启动子活性。活化的STAT因子（STAT），特别是活化的STAT 3，也与GC B细胞中的沉默元件结合并与Bcl 6竞争结合，表明JunD/AP-1和活化的STAT驱动GC B细胞中的高Bcl 6表达。由于用IL-4或IL-21刺激脾B细胞诱导Bcl 6高表达，同时诱导junD和STAT活化，这些细胞因子可能是其在GC B细胞中高表达的诱导剂。然而，IL-21而不是IL-4刺激激活脾B细胞中的STAT 3。因此，IL-21可能是GC B细胞中Bcl 6高表达的主要诱导剂。
The Bcl6 proto-oncogene, which encodes a transcriptional repressor, is ubiquitously expressed and predominantly in germinal center (GC) B cells. Although the promoter region of the human Bcl6 gene has been reported, enhancer molecules for its high expression in GC B cells were largely unknown. Here we show that transcriptional start sites of the murine Bcl6 gene were different from the reported human one. DNA sequence around the new promoter region is highly conserved between mice and humans and has no canonical TATA or CCAAT box. Two AP-1-binding elements in the promoter region were the major enhancer elements in GC-derived B lymphoma cells, and JunD/AP-1 was detected in GC B cells. In addition, we identified the silencer region with three Bcl6-binding elements around the start site. Bcl6 bound to the silencer elements and its over-expression repressed the promoter activity through the elements. Activated STAT factors (STATs), especially activated STAT3, also bound to the silencer elements in GC B cells and competed with Bcl6 for the binding, suggesting that JunD/AP-1 and activated STATs drive high Bcl6 expression in GC B cells. Since stimulation of splenic B cells with IL-4 or IL-21 induced high Bcl6 expression with induction of junD and activation of STATs, these cytokines may be inducers for its high expression in GC B cells. However, IL-21 but not IL-4 stimulation activated STAT3 in splenic B cells. Thus, IL-21 may be a major inducer for high Bcl6 expression in GC B cells.