The p53 pathway is synergized by p38 MAPK signaling to mediate 11,11′-dideoxyverticillin-induced G2/M arrest
The p53 pathway is synergized by p38 MAPK signaling to mediate 11,11′-dideoxyverticillin-induced G2/M arrest
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DOI：
10.1016/j.febslet.2005.05.053
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发表时间：
2005-07-04
期刊：
影响因子：
3.5
通讯作者：
Ding, J
中科院分区：
文献类型：
--
作者：
Chen, Y;Miao, ZH;Ding, J
源自真菌 Shiraia bambusicola 的植物化学物质 11,11'-双脱氧轮枝菌素已被证明在体外和体内具有有效的抗癌活性。在这里，我们研究了 11,11'-双脱氧轮枝菌素对细胞周期进程的影响，并探讨了这种影响的潜在机制。在 11,11'-双脱氧轮菌素治疗后，在人结肠癌细胞 (HCT-116) 中观察到 G(2)/M 期浓度和时间依赖性细胞周期阻断，并且与 p53、磷酸-p53(ser20) 和磷酸-Chk2(Thr 68) 水平的显着增加相关。当通过 RNA 干扰特异性抑制野生型 p53 表达时，用 11,11'-双脱氧轮枝菌素处理的 HCT-116 细胞未能停滞在 G2/M 期，并且没有显示磷酸化 Chk2（Thr 68）增加。另一方面，11,11'-双脱氧轮枝菌素处理也引发 p38 MAP 激酶活性和磷酸化 p38 MAPK 的表达。用特异性 p38 MAPK 抑制剂 (SB203580) 治疗可成功抑制 p38 MAPK，并延迟约 6 小时后 0.5 μM 11,11'-双脱氧轮菌素诱导的 G2/M 停滞的发生，但并未消除 G2/M 停滞的诱导。此外，SB203580 不会改变 11,11'-双脱氧轮枝菌素处理的细胞中 p53、磷酸化 p53 (ser20) 或磷酸化 Chk2 (Thr68) 蛋白的水平。总之，这些发现表明 p53 介导的 Chk2 磷酸化可能在 11, 11-双脱氧轮枝菌素诱导的 G 阻滞中发挥重要作用，并且 p38 MAPK 可能加速这一进程。我们的工作提出了 G(2)/M 停滞中 p53、Chk2 和 p38 MAPK 信号之间相互作用的新可能性。 (c) 2005 年欧洲生化学会联合会。由 Elsevier B.V. 出版。保留所有权利。
The phytochemical 11,11'-dideoxyverticillin, derived from the fungus Shiraia bambusicola, has been shown to possess potent anticancer activity in vitro and in vivo. Here, we investigated the effect of 11,11'-dideoxyverticillin on cell cycle progression, and explored the potential mechanisms for this effect. A concentration- and time-dependent cell cycle blockade at G(2)/M phase was observed in human colon cancer cells (HCT-116) following 11,11'-dideoxyverticillin treatment and was associated with marked increases in levels of p53, phospho-p53(ser20) and phospho-Chk2(Thr 68). When wild type p53 expression was specifically inhibited by RNA interference, HCT-116 cells treated with 11,11'-dideoxyverticillin failed to arrest in G2/M and did not show increased phospho-Chk2(Thr 68). On the other hand, 11,11'-dideoxyverticillin treatment also elicited p38 MAP kinase activity and expression of phospho-p38 MAPK. Treatment with a specific p38 MAPK inhibitor (SB203580) successfully inhibited p38 MAPK and delayed the onset of G2/M arrest induced by 0.5 mu M 11,11'-dideoxyverticillin after approximately 6h, but did not abolish the induction of G2/M arrest. Additionally, SB203580 did not alter the levels of p53, phospho-p53 (ser20), or phospho-Chk2 (Thr68) proteins in 11,11'-dideoxyverticillin-treated cells. Together, these findings indicate that p53-mediated phosphorylation of Chk2 maybe plays a vital role in 11, 11-dideoxyverticillin-induced G arrest, and that p38 MAPK might accelerate this progression. Our work suggests a new possibility of interactions among p53, Chk2 and p38 MAPK signaling in G(2)/M arrest. (c) 2005 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.