Bcl-XL affects Ca2+ horneostasis by altering expression of inositol 1,4,5-trisphosphate receptors
Bcl-XL affects Ca2+ horneostasis by altering expression of inositol 1,4,5-trisphosphate receptors
复制标题
DOI：
10.1073/pnas.152571899
复制
发表时间：
2002-07-23
影响因子：
11.1
通讯作者：
Thompson, CB
中科院分区：
文献类型：
--
作者：
Li, C;Fox, CJ;Thompson, CB
对 9,500 个基因和表达序列标签 (EST) 进行的基于寡核苷酸的微阵列分析表明，与对照细胞相比，表达 Bcl-X-L 的 1 型肌醇 1,4,5-三磷酸受体 (IP3R) 显着下调。通过对两个独立的造血细胞系和鼠原代 T 细胞进行 Northern 和 Western 印迹分析，在 mRNA 和蛋白质水平上证实了这一结果。 Bcl-X-L 表达导致 IP3R 蛋白剂量依赖性减少。 IP3R 表达作为线粒体到细胞核应激反应途径的一部分受到调节。线粒体氧化磷酸化的解偶联导致转录因子 NFATc2 与 IP3R 启动子的结合诱导以及 IP3R 的转录激活。 Bcl-XL 的表达导致 NFATc2 DNA 与 IP3R 启动子结合的诱导减少，以及响应线粒体氧化磷酸化抑制的 IP3R 表达的减少。 Bcl-X-L依赖性IP3R表达的降低还与Bcl-XL转基因小鼠T细胞中T细胞抗原受体连接诱导的Ca2+流量减少相关，并且由BCl-X-L过表达细胞制备的微粒体囊泡表现出较低的IN介导的Ca2+释放能力。此外，将 IP3R 重新引入 Bcl-X-L 转染细胞可部分逆转 Bcl-X-L 依赖性抗凋亡活性。这些结果表明，即使在非凋亡条件下，Bcl-2 家族蛋白的表达也会影响将线粒体代谢变化与核基因表达变化联系起来的信号网络。
An oligonucleotide-based microarray analysis of 9,500 genes and expressed sequence tags (ESTs) demonstrated that the type 1 inositol 1,4,5-trisphosphate receptor (IP3R) was significantly down-regulated in Bcl-X-L-expressing as compared with control cells. This result was confirmed at the mRNA and protein levels by Northern and Western blot analyses of two independent hematopoietic cell lines and murine primary T cells. Bcl-X-L expression resulted in a dose-dependent decrease in IP3R protein. IP3R expression is regulated as part of a mitochondrion-to-nucleus stress-responsive pathway. The uncoupling of mitochondrial oxidative phosphorylation resulted in induction of binding of the transcription factor NFATc2 to the IP3R promoter and transcriptional activation of IP3R. Expression of Bcl-XL led to a decreased induction of both NFATc2 DNA binding to the IP3R promoter and IP3R expression in response to the inhibition of mitochondrial oxidative phosphorylation. The Bcl-X-L-dependent decrease in IP3R expression also correlated with a reduced T cell antigen receptor ligation-induced Ca2+ flux in Bcl-XL transgenic murine T cells, and microsomal vesicles prepared from BCl-X-L-overexpressing cells exhibited lower IN-mediated Ca2+ release capacity. Furthermore, reintroducing IP3R into Bcl-X-L-transfected cells partially reversed Bcl-X-L-dependent anti-apoptotic activity. These results suggest that even under non-apoptotic conditions, expression of Bcl-2-family proteins influences a signaling network that links changes in mitochondrial metabolism to alterations in nuclear gene expression.