Inhibition of ATR protein kinase activity by schisandrin B in DNA damage response.
Inhibition of ATR protein kinase activity by schisandrin B in DNA damage response.
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Schisandrin B对DNA损伤反应中ATR蛋白激酶活性的抑制。
DOI：
10.1093/nar/gkp593
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发表时间：
2009-09
影响因子：
14.9
通讯作者：
Konishi T
中科院分区：
文献类型：
--
作者：
Nishida H;Tatewaki N;Nakajima Y;Magara T;Ko KM;Hamamori Y;Konishi T
ATM和ATR蛋白激酶在细胞DNA损伤反应中起着至关重要的作用。抑制ATM和ATR可导致细胞周期检查点功能的取消。在这方面，预计检查点抑制剂可以作为抗癌化疗/放疗的增敏剂。虽然已经报道了几种ATM抑制剂，但目前还没有atr特异性抑制剂可用。本文报道了五味子有效成分五味子素B （schisandrin B, SchB）对DNA损伤应答中ATR活性的抑制作用。SchB处理显著降低了紫外线照射后A549腺癌细胞的活力。重要的是，SchB处理抑制了ATM和ATR底物的磷酸化水平，以及紫外线暴露细胞中G2/M检查点的活性。免疫亲和纯化的ATR蛋白激酶活性在体外被SchB剂量依赖性地降低（IC50: 7.25 μM），但对ATM、Chk1、PI3K、DNA-PK和mTOR没有抑制作用。在atm缺陷细胞中，SchB显著降低了紫外线诱导的p53和Chk1的磷酸化程度，而siatr处理的细胞则没有。综上所述，我们证明了SchB在细胞DNA损伤后抑制ATR蛋白激酶活性的能力，这在抗癌治疗中具有临床意义。
ATM and ATR protein kinases play a crucial role in cellular DNA damage responses. The inhibition of ATM and ATR can lead to the abolition of the function of cell cycle checkpoints. In this regard, it is expected that checkpoint inhibitors can serve as sensitizing agents for anti-cancer chemo/radiotherapy. Although several ATM inhibitors have been reported, there are no ATR-specific inhibitors currently available. Here, we report the inhibitory effect of schisandrin B (SchB), an active ingredient of Fructus schisandrae, on ATR activity in DNA damage response. SchB treatment significantly decreased the viability of A549 adenocarcinoma cells after UV exposure. Importantly, SchB treatment inhibited both the phosphorylation levels of ATM and ATR substrates, as well as the activity of the G2/M checkpoint in UV-exposed cells. The protein kinase activity of immunoaffinity-purified ATR was dose-dependently decreased by SchB in vitro (IC50: 7.25 μM), but the inhibitory effect was not observed in ATM, Chk1, PI3K, DNA-PK, and mTOR. The extent of UV-induced phosphorylation of p53 and Chk1 was markedly reduced by SchB in ATM-deficient but not siATR-treated cells. Taken together, our demonstration of the ability of SchB to inhibit ATR protein kinase activity following DNA damage in cells has clinical implications in anti-cancer therapy.
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影响因子：
56.9
作者：
Canman, CE;Lim, DS;Siliciano, JD
通讯作者：
Siliciano, JD
影响因子：
56.9
作者：
HOLLSTEIN, M;SIDRANSKY, D;HARRIS, CC
通讯作者：
HARRIS, CC
影响因子：
56.9
作者：
Matsuoka, Shuhei;Ballif, Bryan A.;Elledge, Stephen J.
通讯作者：
Elledge, Stephen J.
影响因子：
2.7
作者：
IP, SP;POON, MKT;KO, KM
通讯作者：
KO, KM
影响因子：
4.8
作者：
Cliby, WA;Lewis, KA;Kaufmann, SH
通讯作者：
Kaufmann, SH