Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, Sendai 981-8555, Japan.
Toxicol Appl Pharmacol. 2013 Nov 15;273(1):90-9. doi: 10.1016/j.taap.2013.08.017. Epub 2013 Aug 28.
Although the aryl hydrocarbon receptor (AHR) and glucocorticoid receptor (GR) play essential roles in mammalian development, stress responses, and other physiological events, crosstalk between these receptors has been the subject of much debate. Metallothioneins are classic glucocorticoid-inducible genes that were reported to increase upon treatment with AHR agonists in rodent tissues and cultured human cells. In this study, the mechanism of human metallothionein 2A (MT2A) gene transcription activation by AHR was investigated. Cotreatment with 3-methylcholanthrene and dexamethasone, agonists of AHR and GR respectively, synergistically increased MT2A mRNA levels in HepG2 cells. MT2A induction was suppressed by RNA interference against AHR or GR. Coimmunoprecipitation experiments revealed a physical interaction between AHR and GR proteins. Moreover, chromatin immunoprecipitation assays indicated that AHR was recruited to the glucocorticoid response element in the MT2A promoter. Thus, we provide a novel mechanism whereby AHR modulates expression of human MT2A via the glucocorticoid response element and protein-protein interactions with GR.
尽管芳香烃受体 (AHR) 和糖皮质激素受体 (GR) 在哺乳动物的发育、应激反应和其他生理事件中发挥着重要作用，但这两个受体之间的相互作用一直是争论的焦点。金属硫蛋白是经典的糖皮质激素诱导基因，据报道，在啮齿动物组织和培养的人细胞中，AHR 激动剂处理后其表达增加。在这项研究中，研究了 AHR 对人金属硫蛋白 2A (MT2A) 基因转录激活的机制。分别用 AHR 和 GR 的激动剂 3-甲基胆蒽和地塞米松共同处理，协同增加了 HepG2 细胞中 MT2A mRNA 的水平。针对 AHR 或 GR 的 RNA 干扰抑制了 MT2A 的诱导。共免疫沉淀实验显示 AHR 和 GR 蛋白之间存在物理相互作用。此外，染色质免疫沉淀分析表明 AHR 被募集到 MT2A 启动子中的糖皮质激素反应元件上。因此，我们提供了一种新的机制，即 AHR 通过糖皮质激素反应元件和与 GR 的蛋白-蛋白相互作用来调节人 MT2A 的表达。
