Lee H H, Dadgostar H, Cheng Q, Shu J, Cheng G
Department of Microbiology and Molecular Genetics, Jonsson Comprehensive Cancer Center, and Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA.
Proc Natl Acad Sci U S A. 1999 Aug 3;96(16):9136-41. doi: 10.1073/pnas.96.16.9136.
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-kappaB pathway by overexpression of a dominant-active inhibitor of NF-kappaB abolished CD40-induced 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-kappaB-binding sequence was found to support NF-kappaB-dependent transcriptional activation. Furthermore, expression of physiological levels of Bcl-x protected B cells from Fas-mediated apoptosis in the absence of NF-kappaB signaling. Thus, our results suggest that CD40-mediated cell survival proceeds through NF-kappaB-dependent up-regulation of Bcl-2 family members.
CD40的激活对于胸腺依赖性体液免疫反应以及挽救B细胞免于凋亡至关重要。CD40的许多效应被认为是通过改变基因表达来实现的。除了已知的CD40调节的抗凋亡分子Bcl-x外，我们还鉴定出一种相关的抗凋亡分子A1/Bfl-1，作为CD40诱导基因。通过过表达NF-κB的显性活性抑制剂来抑制NF-κB途径，消除了CD40诱导的Bfl-1和Bcl-x基因上调，也消除了CD40挽救Fas诱导的细胞死亡的能力。在Bcl-x的上游启动子区域内，发现一个潜在的NF-κB结合序列支持NF-κB依赖性转录激活。此外，在没有NF-κB信号传导的情况下，生理水平的Bcl-x表达可保护B细胞免受Fas介导的凋亡。因此，我们的结果表明，CD40介导的细胞存活是通过NF-κB依赖性上调Bcl-2家族成员来实现的。
