Endosulfan upregulates AP-1 binding and ARE-mediated transcription via ERK1/2 and p38 activation in HepG2 cells.
Endosulfan upregulates AP-1 binding and ARE-mediated transcription via ERK1/2 and p38 activation in HepG2 cells.
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DOI：
10.1016/j.tox.2011.11.013
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发表时间：
2012-02-06
期刊：
影响因子：
4.5
通讯作者：
Freedman, Jonathan H.
中科院分区：
文献类型：
--
作者：
Song, Min Ok;Lee, Chang-Ho;Yang, Hyun Ok;Freedman, Jonathan H.
硫丹是一种有机氯杀虫剂，具有神经毒性、肝毒性、免疫抑制和致畸性。然而，硫丹毒性的分子机制尚不清楚。最近的研究表明，硫丹引起的氧化应激与其毒性有关，越来越多的证据表明，硫丹可以调节包括细胞外信号调节激酶1/2在内的应激反应信号转导途径的活动。然而，以前的研究都没有调查硫丹调节活化蛋白-1结合和抗氧化反应元件介导的转录的能力，这是硫丹毒性的一种潜在机制。在这份报告中，我们表明，治疗HepG 2细胞与硫丹显着增加氧化应激反应转录通过AP-1激活。此外，硫丹诱导的转录增强了细胞中的谷胱甘肽耗尽丁硫醚亚砜（BSO）治疗。接触硫丹导致MAPKs、ERK 1/2和p38的活性显著增加。硫丹诱导的这些MAPK酶活性的增加与MAPK磷酸化一致。接触硫丹也会导致c-Jun磷酸化增加。这些结果表明了硫丹毒性的一个模型，其中硫丹增加了ERK 1/2和p38的活性，这些活化的MAPK随后增加了c-Jun磷酸化。磷酸化的c-Jun反过来增加AP-1活性，这导致ARE介导的转录的激活。
Endosulfan is an organochlorine insecticide and has been implicated in neurotoxicity, hepatotoxicity, immunosuppression and teratogenicity. However, the molecular mechanism of endosulfan toxicity is not yet clear. Recent studies demonstrated that oxidative stress induced by endosulfan is involved in its toxicity and accumulating evidence suggests that endosulfan can modulate the activities of stress-responsive signal transduction pathways including extracellular signal regulated kinases (ERK) 1/2. However, none of the previous studies investigated the ability of endosulfan to modulate activating protein-1 (AP-1) binding and antioxidant response element (ARE)-mediated transcription as an underlying mechanism of endosulfan toxicity. In this report, we show that treatment of HepG2 cells with endosulfan significantly increased oxidative stress-responsive transcription via AP-1 activation. In addition, endosulfan-induced transcription was enhanced in cells depleted of glutathione by buthionine sulfoximine (BSO) treatment. Exposure to endosulfan resulted in a significant increase in the activities of MAPKs, ERK1/2 and p38. Endosulfan-induced increases in enzymatic activities of these MAPKs were consistent with MAPK phosphorylation. Endosulfan exposure also caused an increase in c-Jun phosphorylation. These results suggest a model for endosulfan toxicity in which endosulfan increases ERK1/2 and p38 activities and these activated MAPKs then increase c-Jun phosphorylation. Phosphorylated c-Jun, in turn, increases AP-1 activity, which results in activation of ARE-mediated transcription.
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