Endoplasmic reticulum stress-induced apoptosis - Multiple pathways and activation of p53-up-regulated modulator of apoptosis (PUMA) and NOXA by p53
Endoplasmic reticulum stress-induced apoptosis - Multiple pathways and activation of p53-up-regulated modulator of apoptosis (PUMA) and NOXA by p53
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DOI：
10.1074/jbc.m509868200
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发表时间：
2006-03-17
影响因子：
4.8
通讯作者：
Lee, AS
中科院分区：
文献类型：
--
作者：
Li, JZ;Lee, B;Lee, AS
内质网（ER）应激诱导的细胞凋亡与多种疾病的发生有关。然而，体内信号传导途径仍然没有完全理解。在这份报告中，通过使用遗传缺陷的小鼠胚胎成纤维细胞（MEFs）及其匹配的野生型对照，我们已经证明，线粒体凋亡途径介导的Apaf-1是一个组成部分的ER应力诱导的细胞凋亡和ER应力激活不同的半胱天冬酶通过Apaf-1依赖和独立的机制。在寻找ER应激和线粒体凋亡途径之间的分子联系时，我们发现在MEFs中，ER应激通过肿瘤抑制基因p53在转录水平上选择性地激活仅BH 3的蛋白质NOXA和BH 3-only蛋白质NOXA。在p53（-/-）MEFs中，ER应激诱导的细胞凋亡被部分抑制。p53非依赖性凋亡途径可能由C/EBP同源蛋白（CHOP）和caspase-12介导，因为它们的激活在p53（-/-）MEFs中是完整的。在多个MEF系中，p53主要是核的，并且其水平在ER应激时升高。为了确定NOXA和NOXA A在ER应激诱导的细胞凋亡中的作用，我们已经表明，在NOXA或NOXA A缺陷的MEFs中，ER应激诱导的细胞凋亡减少。可逆地，NOXA或NOXA的过表达诱导细胞凋亡，如通过巴克和半胱天冬酶-7的活化所证明的。我们的研究结果提供了新的证据表明，在MEFs中，除了ESTA，p53和NOXA是ER应激诱导的凋亡途径的新组件，都有助于ER应激诱导的凋亡。
Endoplasmic reticulum ( ER) stress-induced apoptosis has been implicated in the development of multiple diseases. However, the in vivo signaling pathways are still not fully understood. In this report, through the use of genetically deficient mouse embryo fibroblasts (MEFs) and their matched wild-type controls, we have demonstrated that the mitochondrial apoptotic pathway mediated by Apaf-1 is an integral part of ER stress-induced apoptosis and that ER stress activates different caspases through Apaf-1-dependent and - independent mechanisms. In search of the molecular link between ER stress and the mitochondrial apoptotic pathway, we have discovered that in MEFs, ER stress selectively activates BH3-only proteins PUMA and NOXA at the transcript level through the tumor suppressor gene p53. In p53(-/-) MEFs, ER stress-induced apoptosis is partially suppressed. The p53-independent apoptotic pathway may be mediated by C/EBP homologous protein ( CHOP) and caspase-12, as their activation is intact in p53(-/-) MEFs. In multiple MEF lines, p53 is primarily nuclear and its level is elevated upon ER stress. To establish the role of NOXA and PUMA in ER stress-induced apoptosis, we have shown that, in MEFs deficient in NOXA or PUMA, ER stress-induced apoptosis is reduced. Reversibly, overexpression of NOXA or PUMA induces apoptosis as evidenced by the activation of BAK and caspase-7. Our results provide new evidence that, in MEFs, in addition to PUMA, p53 and NOXA are novel components of the ER stress-induced apoptotic pathway, and both contribute to ER stress-induced apoptosis.