Interdependence of Bad and Puma during ionizing-radiation-induced apoptosis.
Interdependence of Bad and Puma during ionizing-radiation-induced apoptosis.
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DOI：
10.1371/journal.pone.0088151
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Jette C
中科院分区：
文献类型：
--
作者：
Toruno C;Carbonneau S;Stewart RA;Jette C
电离辐射(IR)诱导的DNA双链断裂引发了广泛的细胞信号反应，涉及数百种蛋白质的协调作用，以调节DNA修复、细胞周期停滞和凋亡途径。细胞的结果通常取决于DNA损伤的程度以及特定的细胞类型。增殖的斑马鱼胚胎神经元对IR诱导的细胞凋亡高度敏感，而P53及其转录靶标PUMA都是这种反应的重要中介。此前报道，BH3-Only蛋白Puma通过与促凋亡蛋白Bax和Bak直接相互作用而激活线粒体凋亡，从而构成BH3-Only蛋白的“激活”角色。这与BH3-Only蛋白质不同，Bad等蛋白质被认为通过与抗凋亡的Bcl-2家族成员结合来间接促进细胞凋亡，从而防止仅激活BH3的蛋白质被隔离，并允许它们直接与Bax和Bak相互作用和激活。我们以前已经证明，在斑马鱼胚胎中过表达BH3-Only蛋白Bad支持正常的胚胎发育，但极大地增强了发育中的神经元对IR诱导的细胞凋亡的敏感性。虽然Bad之前被证明在促进IR诱导的小鼠T细胞凋亡方面只起到很小的作用，但我们证明了Bad对于IR诱导斑马鱼胚胎神经组织的强大的凋亡是必不可少的。此外，我们发现P53和PUMA都是Bad介导的体内放射增敏所必需的。我们的发现表明，Bad和Puma之间存在等级相互依赖关系，Bad是IR诱导的线粒体凋亡的基本敏感剂，Puma是IR诱导的线粒体凋亡的基本激活剂，尤其是在胚胎神经组织中。
Ionizing radiation (IR)-induced DNA double-strand breaks trigger an extensive cellular signaling response that involves the coordination of hundreds of proteins to regulate DNA repair, cell cycle arrest and apoptotic pathways. The cellular outcome often depends on the level of DNA damage as well as the particular cell type. Proliferating zebrafish embryonic neurons are highly sensitive to IR-induced apoptosis, and both p53 and its transcriptional target puma are essential mediators of the response. The BH3-only protein Puma has previously been reported to activate mitochondrial apoptosis through direct interaction with the pro-apoptotic Bcl-2 family proteins Bax and Bak, thus constituting the role of an “activator” BH3-only protein. This distinguishes it from BH3-only proteins like Bad that are thought to indirectly promote apoptosis through binding to anti-apoptotic Bcl-2 family members, thereby preventing the sequestration of activator BH3-only proteins and allowing them to directly interact with and activate Bax and Bak. We have shown previously that overexpression of the BH3-only protein Bad in zebrafish embryos supports normal embryonic development but greatly sensitizes developing neurons to IR-induced apoptosis. While Bad has previously been shown to play only a minor role in promoting IR-induced apoptosis of T cells in mice, we demonstrate that Bad is essential for robust IR-induced apoptosis in zebrafish embryonic neural tissue. Moreover, we found that both p53 and Puma are required for Bad-mediated radiosensitization in vivo. Our findings show the existence of a hierarchical interdependence between Bad and Puma whereby Bad functions as an essential sensitizer and Puma as an essential activator of IR-induced mitochondrial apoptosis specifically in embryonic neural tissue.
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影响因子：
4.8
作者：
Ottilie, S;Diaz, JL;Oltersdorf, T
通讯作者：
Oltersdorf, T
影响因子：
16
作者：
Ciccia A;Elledge SJ
通讯作者：
Elledge SJ
影响因子：
12.4
作者：
Kratz, E.;Eimon, P. M.;Ashkenazi, A.
通讯作者：
Ashkenazi, A.
DOI：
10.1073/pnas.0406252102
发表时间：
2005-01-11
影响因子：
11.1
作者：
Berghmans, S;Murphey, RD;Look, AT
通讯作者：
Look, AT
影响因子：
5.3
作者：
Chiang, CW;Kanies, C;Yang, E
通讯作者：
Yang, E