Tanshinone IIA triggers p53 responses and apoptosis by RNA polymerase II upon DNA minor groove binding.
Tanshinone IIA triggers p53 responses and apoptosis by RNA polymerase II upon DNA minor groove binding.
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丹参酮 IIA 在 DNA 小沟结合后通过 RNA 聚合酶 II 触发 p53 反应和细胞凋亡。
DOI：
10.1016/j.bcp.2009.06.110
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发表时间：
2009-11
影响因子：
5.8
通讯作者：
Zhichao Zhang, Jin Gao, Ting Song
中科院分区：
文献类型：
--
作者：
Zhichao Zhang, Jin Gao, Ting Song
我们之前的研究表明，丹参酮IIA （Tan IIA）是一种DNA小凹槽结合剂，而不是以前认为的插入剂。在本研究中，我们进一步证明了Tan IIA的分子抗肿瘤药理作用依赖于其凹槽结合能力。首先，我们利用圆二色光谱研究了Tan IIA结合对双链DNA的结构损伤。随后，我们通过western blot、流式细胞术分析、染色质免疫沉淀和定量实时PCR来说明RNAPII在暴露于Tan IIA的H22细胞中的降解、磷酸化和沿转录基因的分布。此外，我们还测量了Tan IIA对培养的H22细胞和腹水型H22小鼠的p53激活和凋亡诱导。结果表明，Tan IIA通过改变DNA结构来降低RNAPII的水平。在低剂量范围（0.2 ~ 4μ m）的Tan IIA暴露下，DNA结构损伤导致RNAPII与DNA的结合受到抑制，RNAPII开始磷酸化，而较高浓度（4 ~ 20μ m）的Tan IIA暴露会导致RNAPII完全磷酸化和降解，进而导致p53活化和凋亡。RNAPII在动物中也有类似的细胞凋亡诱导作用。直到Tan IIA下调RNAPII水平后，腹水中肿瘤细胞的凋亡才被检测到，这需要40mg/kg体重的Tan IIA。综上所述，dna构象损伤依赖性RNAPII对凹槽结合的反应是Tan IIA体内和体外抗肿瘤特性的分子基础。
Our previous work has shown that tanshinone IIA (Tan IIA) is a DNA minor groove binder instead of an intercalator as previously thought. In this study, we have further demonstrated that the molecular antitumor pharmacology of Tan IIA is dependent on its groove-binding capability. First, we investigated the structure damage to duplex DNA upon Tan IIA binding using circular dichroism spectra. Subsequently, we performed western blot, flow cytometry analysis, chromatin immunoprecipitation, and quantitative real-time PCR to illustrate the RNAPII degradation, phosphorylation, and distribution along the transcribed gene in H22 cells exposed to Tan IIA. In addition, p53 activation and apoptosis induction in both cultured H22 cells and in mice bearing the ascitic-type H22 were measured following Tan IIA treatment. It was revealed that Tan IIA decreases the level of RNAPII by altering DNA structure. At the low dose range (0.2–4μM) of Tan IIA exposure, the DNA structure damage results in the inhibition of RNAPII binding to DNA and the initiation of RNAPII phosphorylation, while higher concentrations of Tan IIA (4–20μM) cause complete phosphorylation and degradation of RNAPII followed by p53 activation and apoptosis. A similar apoptosis induction by RNAPII was observed in animals. Apoptosis of tumor cells from ascitic fluid was not detected until RNAPII levels were downregulated by Tan IIA, which requires 40mg/kg body weight of Tan IIA. It was concluded that DNA-conformational-damage-dependent RNAPII response upon groove binding is the molecular basis of the antitumor property of Tan IIA, in vivo and in vitro.
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影响因子：
3.8
作者：
D. Scicchitano;E. Olesnicky;A. Dimitri
通讯作者：
D. Scicchitano;E. Olesnicky;A. Dimitri
DOI：
10.1016/s0921-8777(01)00097-0
发表时间：
2001-09-04
期刊：
MUTATION RESEARCH-DNA REPAIR
影响因子：
--
作者：
Luo, ZH;Zheng, JH;Bregman, DB
通讯作者：
Bregman, DB
影响因子：
5.1
作者：
Xiujie Wang;S. Yuan;Chao-jun Wang;Renmin Huang;Yuqiong Li
通讯作者：
Xiujie Wang;S. Yuan;Chao-jun Wang;Renmin Huang;Yuqiong Li
影响因子：
13.3
作者：
Wang, Xihong;Morris-Natschke, Susan L.;Lee, Kuo-Hsiung
通讯作者：
Lee, Kuo-Hsiung
影响因子：
5.6
作者：
Khobta, A;Ferri, F;Capranico, G
通讯作者：
Capranico, G