BAG3 sensitizes cancer cells exposed to DNA damaging agents via direct interaction with GRP78
BAG3 sensitizes cancer cells exposed to DNA damaging agents via direct interaction with GRP78
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BAG3 通过与 GRP78 直接相互作用使暴露于 DNA 损伤剂的癌细胞变得敏感
DOI：
10.1016/j.bbamcr.2013.09.013
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发表时间：
2013-12-01
影响因子：
5.1
通讯作者：
Wang, Hua-Qin
中科院分区：
文献类型：
--
作者：
Kong, De-Hui;Zhang, Qiang;Wang, Hua-Qin
BCL-2相关基因3(BAG3)具有一个模块化结构，它包含一个BAG结构域、一个WW结构域、一个富含Pro的结构域(PxxP)，以介导与伴侣和其他参与多种信号转导的蛋白质之间的潜在相互作用。为了寻找新的相互作用伙伴，本研究确定78 kDa葡萄糖调节蛋白(GRP78)是一个与BAG3相互作用的新伙伴。免疫共沉淀和谷胱甘肽S转移酶下拉实验证实了GRP78与Bag3的相互作用。我们还发现GRP78的ATPase结构域和BAG3的BAG结构域介导了它们之间的相互作用。BAG3作为一种生存蛋白，被发现在基因毒性压力下促进乳腺癌MCF7、甲状腺癌FOR和胶质瘤U87细胞的细胞毒作用，这与直觉相反。此外，目前的研究表明，BAG3干扰了抗凋亡的GRP78-proaspase-7复合体的形成，从而导致了肿瘤细胞中遗传毒性应激诱导的细胞毒性增加。此外，GRP78的过表达显著阻断了BAG3对caspase-7的激活和遗传毒性应激诱导的细胞凋亡的增强作用。总之，这些结果表明，BAG3可以通过直接相互作用来阻止GRP78对遗传毒性应激的抗凋亡作用。(C)2013爱思唯尔B.V.保留所有权利。
Bcl-2 associated athanogene 3 (BAG3) has a modular structure that contains a BAG domain, a WW domain, a proline-rich (PxxP) domain to mediate potential interactions with chaperons and other proteins that participate in more than one signal transduction. In search for novel interacting partners, the current study identified that 78 kDa glucose-regulated protein (GRP78) was a novel partner interacting with BAG3. Interaction between GRP78 and BAG3 was confirmed by coimmunoprecipitation and glutathione S-transferase (GST) pulldown. We also identified that the ATPase domain of GRP78 and BAG domain of BAG3 mediated their interaction. Counter-intuitive for a prosurvival protein, BAG3 was found to promote the cytotoxicity of breast cancer MCF7, thyroid cancer FRO and glioma U87 cells subjected to genotoxic stress. In addition, the current study demonstrated that BAG3 interfered with the formation of the antiapoptotic GRP78-procaspase-7 complex, which resulted in an increased genotoxic stress-induced cytotoxicity in cancer cells. Furthermore, overexpression of GRP78 significantly blocked the enhancing effects of BAG3 on activation of caspase-7 and induction of apoptosis by genotoxic stress. Overall, these results suggested that through direct interaction BAG3 could prevent the antiapoptotic effect of GRP78 upon genotoxic stress. (C) 2013 Elsevier B.V. All rights reserved.