The organochlorine o,p'-DDT plays a role in coactivator-mediated MAPK crosstalk in MCF-7 breast cancer cells.
The organochlorine o,p'-DDT plays a role in coactivator-mediated MAPK crosstalk in MCF-7 breast cancer cells.
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DOI：
10.1289/ehp.1104296
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发表时间：
2012-09
影响因子：
10.4
通讯作者：
Burow ME
中科院分区：
文献类型：
--
作者：
Bratton MR;Frigo DE;Segar HC;Nephew KP;McLachlan JA;Wiese TE;Burow ME
背景资料：有机氯二氯二苯三氯乙烷（DDT）是一种已知的雌激素模拟物和内分泌干扰物，与动物和人类疾病有关。然而，DDT影响细胞生理学的详细机制仍然没有完全确定。目的：我们和其他人已经表明，DDT激活细胞信号级联，最终激活雌激素受体依赖和非依赖基因表达。在这里，我们确定了DDT改变细胞信号和基因表达的机制，独立于雌激素受体。研究方法：我们使用雌二醇（E2）或o，p ′-DDT对MCF-7乳腺癌细胞中的基因表达进行了定量聚合酶链反应阵列分析，以确定不同的细胞基因表达反应。为了阐明DDT调节细胞信号传导的机制，我们使用了分子和药理学技术。结果如下：E2和DDT处理都改变了许多基因的表达，但血管内皮生长因子A（VEGFA）的上调仅在DDT处理后观察到，这种增加不受纯雌激素受体α拮抗剂ICI 182780的影响。此外，DDT增加了HIF-1反应元件（HRE）的激活，这是一种已知的VEGFA基因增强子。这种DDT介导的HRE活性增加由共激活因子CBP（CREB结合蛋白）增强，并依赖于p38通路。结论：DDT上调了MCF-7乳腺癌细胞中几个基因的表达，这些基因没有被E2治疗改变，包括VEGFA。我们建议，这种DDT启动，ER独立的刺激基因表达是由于DDT的能力，启动MAPK（丝裂原活化蛋白激酶）信号通路和转录辅激活因子之间的串扰。
Background: The organochlorine dichlorodiphenyltrichloroethane (DDT), a known estrogen mimic and endocrine disruptor, has been linked to animal and human disorders. However, the detailed mechanism(s) by which DDT affects cellular physiology remains incompletely defined. Objectives: We and others have shown that DDT activates cell-signaling cascades, culminating in the activation of estrogen receptor-dependent and -independent gene expression. Here, we identify a mechanism by which DDT alters cellular signaling and gene expression, independent of the estrogen receptor. Methods: We performed quantitative polymerase chain reaction array analysis of gene expression in MCF-7 breast cancer cells using either estradiol (E2) or o,p´-DDT to identify distinct cellular gene expression responses. To elucidate the mechanisms by which DDT regulates cell signaling, we used molecular and pharmacological techniques. Results: E2 and DDT treatment both altered the expression of many of the genes assayed, but up-regulation of vascular endothelial growth factor A (VEGFA) was observed only after DDT treatment, and this increase was not affected by the pure estrogen receptor α antagonist ICI 182780. Furthermore, DDT increased activation of the HIF-1 response element (HRE), a known enhancer of the VEGFA gene. This DDT-mediated increase in HRE activity was augmented by the coactivator CBP (CREB-binding protein) and was dependent on the p38 pathway. Conclusions: DDT up-regulated the expression of several genes in MCF-7 breast cancer cells that were not altered by treatment with E2, including VEGFA. We propose that this DDT-initiated, ER-independent stimulation of gene expression is due to DDT’s ability to initiate crosstalk between MAPK (mitogen-activated protein kinase) signaling pathways and transcriptional coactivators.
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影响因子：
11.4
作者：
Ema, M;Hirota, K;Fujii-Kuriyama, Y
通讯作者：
Fujii-Kuriyama, Y
影响因子：
10.4
作者：
Frigo, Daniel E;Burow, Matthew E;Mitchell, Kamron A;Chiang, Tung-Chin;McLachlan, John A
通讯作者：
McLachlan, John A
影响因子：
10.4
作者：
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通讯作者：
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DOI：
10.1073/pnas.93.23.12969
发表时间：
1996-11-12
影响因子：
11.1
作者：
Arany, Z;Huang, LE;Livingston, DM
通讯作者：
Livingston, DM
影响因子：
--
作者：
Frigo, DE;Basu, A;Burow, ME
通讯作者：
Burow, ME