NF-κB-mediated up-regulation of Bcl-x and Bfl-1/A1 is required for CD40 survival signaling in B lymphocytes
NF-κB-mediated up-regulation of Bcl-x and Bfl-1/A1 is required for CD40 survival signaling in B lymphocytes
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DOI：
10.1073/pnas.96.16.9136
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发表时间：
1999-08-03
影响因子：
11.1
通讯作者：
Cheng, GH
中科院分区：
文献类型：
--
作者：
Lee, HH;Dadgostar, H;Cheng, GH
CD40的活化对于胸腺依赖性体液免疫应答和拯救B细胞免于凋亡是必不可少的。CD40的许多作用被认为是通过改变基因表达来实现的。除了Bcl-x，一种已知的CD40调节的抗凋亡分子，我们确定了一个相关的抗凋亡分子，A1/Bfl-1，作为一个CD40诱导基因。通过过度表达NF-κ B的显性活性抑制剂来抑制NF-κ B通路，可以消除CD 40诱导的Bfl-1和Bcl-x基因的上调，也消除了CD 40拯救Fas诱导的细胞死亡的能力。在Bcl-x的上游启动子区域内，发现潜在的NF-κ B结合序列支持NF-κ B依赖性转录激活。此外，在NF-κ B B信号传导缺失的情况下，生理水平的Bcl-x表达保护B细胞免于Fas介导的凋亡。因此，我们的研究结果表明，CD40介导的细胞存活通过NP-kappa B依赖的Bcl-2家族成员的上调进行。
Activation of CD40 is essential for thymus-dependent humoral immune responses and rescuing B cells from apoptosis. Many of the effects of CD40 are believed to be achieved through altered gene expression. In addition to Bcl-x, a known CD40-regulated antiapoptotic molecule, we identified a related antiapoptotic molecule, A1/Bfl-1, as a CD40-inducible gene. Inhibition of the NF-kappa B pathway by overexpression of a dominant-active inhibitor of NF-kappa B abolished CD40-indueed up-regulation of both the Bfl-1 and Bcl-x genes and also eliminated the ability of CD40 to rescue Fas-induced cell death. Within the upstream promoter region of Bcl-x, a potential NF-kappa B-binding sequence was found to support NF kappa B-dependent transcriptional activation. Furthermore, expression of physiological levels of Bcl-x protected B cells from Fas-mediated apoptosis in the absence of NF-kappa B signaling. Thus, our results suggest that CD40-mediated cell survival proceeds through NP-kappa B-dependent up-regulation of Bcl-2 family members.