Craxton Andrew, Draves Kevin E, Clark Edward A
Department of Microbiology, University of Washington, Seattle, WA 98195, USA.
Eur J Immunol. 2007 Oct;37(10):2715-22. doi: 10.1002/eji.200737327.
BH3-only Bcl-2 homologs are key regulators of the intrinsic apoptotic pathway. In particular, Bim, is critical for mediating apoptosis of hematopoietic cells including B cells. While studies using Bcl-2 Tg mice have defined an important role for Bcl-2 in cell cycle control, the role of BH3-only proteins is less clear. Using Bim KO mice, we show that Bim is required for B cells to enter the cell cycle normally. Bim KO B cells had reduced cell division compared to WT B cells in response to BCR, TLR3 or TLR4 signaling, whereas Bim deficiency did not affect TLR9-induced B cell division. Cell cycle progression in BCR- and LPS-stimulated Bim KO B cells was blocked at the G0-G1 stage. BCR-induced p130 degradation and pRb hyperphosphorylation on Ser807/811, which are critical for G1 entry, were reduced in Bim KO compared to WT B cells. Likewise, BCR-induced p27(Kip1) degradation was decreased in Bim KO compared to WT B cells. These defects in BCR-induced cell cycle entry correlated with a proximal defect in BCR-mediated intracellular calcium release in Bim KO B cells. Our results suggest that the balance of pro- and anti-apoptotic Bcl-2 family proteins is critical for controlling both cell cycle progression and apoptosis in B cells.
仅含BH3结构域的Bcl-2同源物是内源性凋亡途径的关键调节因子。特别是Bim，对于介导包括B细胞在内的造血细胞凋亡至关重要。虽然使用Bcl-2转基因小鼠的研究已经确定了Bcl-2在细胞周期控制中的重要作用，但仅含BH3结构域蛋白的作用尚不清楚。利用Bim基因敲除小鼠，我们发现Bim是B细胞正常进入细胞周期所必需的。与野生型B细胞相比，Bim基因敲除的B细胞在受到BCR、TLR3或TLR4信号刺激时细胞分裂减少，而Bim缺陷并不影响TLR9诱导的B细胞分裂。在BCR和LPS刺激下，Bim基因敲除的B细胞的细胞周期进程在G0-G1期受阻。与野生型B细胞相比，Bim基因敲除的B细胞中BCR诱导的p130降解以及Ser807/811位点的pRb过度磷酸化减少，而这两者对于进入G1期至关重要。同样，与野生型B细胞相比，Bim基因敲除的B细胞中BCR诱导的p27（Kip1）降解减少。BCR诱导的细胞周期进入缺陷与Bim基因敲除的B细胞中BCR介导的细胞内钙释放的近端缺陷相关。我们的结果表明，促凋亡和抗凋亡Bcl-2家族蛋白的平衡对于控制B细胞的细胞周期进程和凋亡至关重要。
