Ligand-dependent and independent modulation of aryl hydrocarbon receptor localization, degradation, and gene regulation.
Ligand-dependent and independent modulation of aryl hydrocarbon receptor localization, degradation, and gene regulation.
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DOI：
10.1124/mol.62.4.806
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发表时间：
2002-10
影响因子：
3.6
通讯作者：
Zhijuan Song;R. Pollenz
中科院分区：
文献类型：
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作者：
Zhijuan Song;R. Pollenz
参与信号转导途径的关键蛋白质的浓度或亚细胞位置的变化已被证明会影响基因调控。研究旨在评估芳烃受体（AHR）的定位，稳定性和基因调控之间的关系，在一个确定的系统中，内源性AHR蛋白可以进行评估。研究结果表明，格尔德霉素（GA）或MG-132（26 S蛋白酶体抑制剂）处理细胞的结果在人HepG 2和小鼠Hepa-1细胞中的内源性AHR的核转位，而不诱导内源性CYP 1A 1蛋白。暴露于GA导致AHR在细胞核中通过26 S蛋白酶体降解>90%。重要的是，AHR水平降低导致2，3，7，8-四氯二苯并-对-二恶英（TCDD）诱导的CYP 1A 1最大水平降低50%。在所有处理中，AHR核转运蛋白（ARNT）蛋白的浓度不变，对AHR的定位没有影响。因此，不依赖配体的AHR易位到细胞核是不足以诱导CYP 1A 1在配体的情况下，但内源性AHR蛋白池水平的降低移动TCDD的剂量-反应曲线的权利。
Changes in the concentration or subcellular location of the key proteins involved in signal transduction pathways have been shown to impact gene regulation. Studies were designed to evaluate the relationship between aryl hydrocarbon receptor (AHR) localization, stability, and gene regulation in a defined system where the endogenous AHR protein could be evaluated. The findings indicate that treatment of cells with geldanamycin (GA) or MG-132 (an inhibitor of the 26S proteasome) results in nuclear translocation of the endogenous AHR in both human HepG2 and murine Hepa-1 cells without induction of endogenous CYP1A1 protein. Exposure to GA resulted in the degradation of AHR by >90% in the nucleus via the 26S proteasome. Importantly, the reduced level of AHR resulted in a 50% reduction in the maximal level of CYP1A1 induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In all treatments the concentration of the AHR nuclear translocator (ARNT) protein was unchanged and had no impact on the localization of the AHR. Thus, ligand-independent translocation of the AHR to the nucleus was not sufficient to induce CYP1A1 in the absence of ligand, but reductions in the level of the endogenous AHR protein pool shifted the dose-response curve for TCDD to the right.