Cell death by SecTRAPs: thioredoxin reductase as a prooxidant killer of cells.
Cell death by SecTRAPs: thioredoxin reductase as a prooxidant killer of cells.
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DOI：
10.1371/journal.pone.0001846
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发表时间：
2008-04-02
期刊：
影响因子：
3.7
通讯作者：
Arnér ES
中科院分区：
文献类型：
--
作者：
Anestål K;Prast-Nielsen S;Cenas N;Arnér ES
SecTRAPs（硒受损硫氧还蛋白还原酶衍生的凋亡蛋白）可以通过用亲电试剂靶向其硒代半胱氨酸（Sec）残基或通过C-末端截短将其去除而由硒蛋白硫氧还蛋白还原酶（TrxR）形成。SecTRAPs缺乏硫氧还蛋白还原酶活性，但可以通过功能的获得在培养的癌细胞系中诱导快速细胞死亡。人和大鼠SecTRAPs都能杀死人A549和HeLa细胞。细胞死亡表现出凋亡和坏死的特点。它不需要新的蛋白质合成，也没有显示出广泛的核碎片，但它是通过使用半胱天冬酶抑制剂减弱。必须维持TrxR的N-末端结构域中的氧化还原活性二硫化物/二硫醇基序以显示SecTRAP细胞毒性。停流动力学表明，NADPH可以以与天然TrxR相似的速率还原SecTRAPs中的FAD部分，并且纯化的SecTRAPs可以保持NADPH氧化酶活性，这被低分子量底物如胡桃醌加速。在细胞环境中，SecTRAPs触发了活性氧（ROS）的广泛形成，因此抗氧化剂可以保护细胞免受SecTRAPs的杀伤。我们得出结论，SecTRAPs的形成可能有助于细胞暴露于靶向TrxR的亲电子试剂后观察到的细胞毒性。SecTRAPs是细胞的促氧化剂杀手，其触发机制超出仅仅丧失硫氧还蛋白还原酶活性的机制。
SecTRAPs (selenium compromised thioredoxin reductase-derived apoptotic proteins) can be formed from the selenoprotein thioredoxin reductase (TrxR) by targeting of its selenocysteine (Sec) residue with electrophiles, or by its removal through C-terminal truncation. SecTRAPs are devoid of thioredoxin reductase activity but can induce rapid cell death in cultured cancer cell lines by a gain of function. Both human and rat SecTRAPs killed human A549 and HeLa cells. The cell death displayed both apoptotic and necrotic features. It did not require novel protein synthesis nor did it show extensive nuclear fragmentation, but it was attenuated by use of caspase inhibitors. The redox active disulfide/dithiol motif in the N-terminal domain of TrxR had to be maintained for manifestation of SecTRAP cytotoxicity. Stopped-flow kinetics showed that NADPH can reduce the FAD moiety in SecTRAPs at similar rates as in native TrxR and purified SecTRAPs could maintain NADPH oxidase activity, which was accelerated by low molecular weight substrates such as juglone. In a cellular context, SecTRAPs triggered extensive formation of reactive oxygen species (ROS) and consequently antioxidants could protect against the cell killing by SecTRAPs. We conclude that formation of SecTRAPs could contribute to the cytotoxicity seen upon exposure of cells to electrophilic agents targeting TrxR. SecTRAPs are prooxidant killers of cells, triggering mechanisms beyond those of a mere loss of thioredoxin reductase activity.
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影响因子：
6.4
作者：
Berndtsson, Maria;Hagg, Maria;Linder, Stig
通讯作者：
Linder, Stig
影响因子：
4.8
作者：
Cenas, N;Prast, S;Arnér, ESJ
通讯作者：
Arnér, ESJ
DOI：
10.1073/pnas.86.7.2172
发表时间：
1989-04-01
影响因子：
11.1
作者：
CHUNG, CT;NIEMELA, SL;MILLER, RH
通讯作者：
MILLER, RH
影响因子：
4.8
作者：
Enoksson, M;Robertson, JD;Orrenius, S
通讯作者：
Orrenius, S
影响因子：
4.8
作者：
Gromer, S;Arscott, LD;Becker, K
通讯作者：
Becker, K