Thromboxane A2 modulates cisplatin-induced apoptosis through a Siva1-dependent mechanism
Thromboxane A2 modulates cisplatin-induced apoptosis through a Siva1-dependent mechanism
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DOI：
10.1038/cdd.2012.11
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发表时间：
2012-08-01
影响因子：
12.4
通讯作者：
Parent, J-L
中科院分区：
文献类型：
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作者：
Iorio-Morin, C.;Germain, P.;Parent, J-L
血栓素A（2）（TXA（2））是一种重要的脂质介质，其在细胞凋亡中的功能是相互矛盾的报告的主题。在这里，酵母双杂交筛选与TXA（2）受体（TP）的C末端相互作用的蛋白质，将Siva 1鉴定为一种新的TP相互作用蛋白。矛盾的证据表明Siva 1的促凋亡和抗凋亡作用。我们发现顺铂处理诱导HeLa细胞合成TXA（2）。我们证明，内源性TP刺激促进顺铂诱导的HeLa细胞凋亡，这种调制需要Siva 1的表达，通过使用siRNA抑制其内源性表达证明。我们发现，在TP的刺激下，Siva 1的降解受到阻碍，导致蛋白质的积累，从细胞核易位到胞质溶胶。Siva 1的易位与其与Mdm 2（p53信号传导抑制剂）的相互作用减少以及与TRAF 2和XIAP（已知增强促凋亡信号传导）的相互作用增加相关。我们的数据提供了一个模型，调和了Siva 1的促凋亡和抗凋亡作用，并确定了G蛋白偶联受体促进凋亡的新机制。我们的研究结果可能对顺铂化疗期间使用环氧合酶抑制剂有意义，并可能提供一个减少顺铂对非癌组织毒性的靶点。Cell Death and Differentiation（2012）19，1347-1357; doi：10.1038/cdd.2012.11; 2012年2月17日在线发表
Thromboxane A(2) (TXA(2)) is an important lipid mediator whose function in apoptosis is the subject of conflicting reports. Here, a yeast two-hybrid screen for proteins that interact with the C-terminus of the TXA(2) receptor (TP) identified Siva1 as a new TP-interacting protein. Contradictory evidence suggests pro-and anti-apoptotic roles for Siva1. We show that a cisplatin treatment induces TXA(2) synthesis in HeLa cells. We demonstrate that endogenous TP stimulation promotes cisplatin-induced apoptosis of HeLa cells and that such modulation requires the expression of Siva1, as evidenced by inhibiting its endogenous expression using siRNAs. We reveal that, upon stimulation of TP, degradation of Siva1 is impeded, resulting in an accumulation of the protein, which translocates from the nucleus to the cytosol. Translocation of Siva1 correlates with its reduced interaction with Mdm2 (an inhibitor of p53 signalling), as well as with its increased interaction with TRAF2 and XIAP (known to enhance pro-apoptotic signalling). Our data provide a model that reconciles the pro-and anti-apoptotic roles that were reported for Siva1 and identify a new mechanism for promoting apoptosis by G protein-coupled receptors. Our findings may have implications in the use of cyclo-oxygenase inhibitors during cisplatin chemotherapy and might provide a target to reduce cisplatin toxicity on non-cancerous tissues. Cell Death and Differentiation (2012) 19, 1347-1357; doi:10.1038/cdd.2012.11; published online 17 February 2012