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首页> 外文期刊>Molecular and Cellular Biology >Proteasome Inhibition Induces Nuclear Translocation and Transcriptional Activation of the Dioxin Receptor in Mouse Embryo Primary Fibroblasts in the Absence of Xenobiotics
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Proteasome Inhibition Induces Nuclear Translocation and Transcriptional Activation of the Dioxin Receptor in Mouse Embryo Primary Fibroblasts in the Absence of Xenobiotics

机译：蛋白酶体抑制诱导异种生物的缺乏小鼠胚胎原代成纤维细胞中二恶英受体的核易位和转录激活。

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The aryl hydrocarbon receptor (AHR) is a transcription factor that is highly conserved during evolution and shares important structural features with the Drosophila developmental regulatorsSim and Per. Although much is known about the mechanism of AHR activation by xenobiotics, little information is available regarding its activation by endogenous stimuli in the absence of exogenous ligand. In this study, using embryonic primary fibroblasts, we have analyzed the role of proteasome inhibition on AHR transcriptional activation in the absence of xenobiotics. Proteasome inhibition markedly reduced cytosolic AHR without affecting its total cellular content. Cytosolic AHR depletion was the result of receptor translocation into the nuclear compartment, as shown by transient transfection of a green fluorescent protein-tagged AHR and by immunoblot analysis of nuclear extracts. Gel retardation experiments showed that proteasome inhibition induced transcriptionally active AHR-ARNT heterodimers able to bind to a consensus xenobiotic-responsive element. Furthermore, nuclear AHR was transcriptionally active in vivo, as shown by the induction of the endogenous target gene CYP1A2. Synchronized to AHR activation, proteasome inhibition also induced a transient increase in AHR nuclear translocator (ARNT) at the protein and mRNA levels. Since nuclear levels of AHR and ARNT are relevant for AHR transcriptional activation, our data suggest that proteasome inhibition, through a transient increase in ARNT expression, could promote AHR stabilization and accumulation into the nuclear compartment. An elevated content of nuclear AHR could favor AHR-ARNT heterodimers able to bind to xenobiotic-responsive elements and to induce gene transcription in the absence of xenobiotics. Thus, depending on the cellular context, physiologically regulated proteasome activity could participate in the control of endogenous AHR functions.
机译：芳烃受体（AHR）是一种转录因子，在进化过程中高度保守，并与果蝇（ems果蝇）发育调节剂 Sim 和 Per 。尽管关于异种生物激活AHR的机制知之甚少，但在缺乏外源配体的情况下，有关内源性刺激激活AHR的信息很少。在这项研究中，使用胚胎原代成纤维细胞，我们分析了在没有异源生物的情况下蛋白酶体抑制对AHR转录激活的作用。蛋白酶体抑制作用显着降低了胞质AHR，而不会影响其总细胞含量。胞浆AHR耗竭是受体易位进入核区室的结果，如绿色荧光蛋白标记的AHR的瞬时转染和核提取物的免疫印迹分析所示。凝胶阻滞实验表明，蛋白酶体抑制作用诱导转录活性AHR-ARNT异二聚体能够结合共有的异源生物响应元件。此外，如诱导内源性靶基因CYP1A2所示，核AHR在体内具有转录活性。与AHR激活同步，蛋白酶体抑制作用还导致AHR核转运蛋白（ARNT）在蛋白质和mRNA水平上的瞬时增加。由于AHR和ARNT的核水平与AHR转录激活有关，因此我们的数据表明，蛋白酶体的抑制通过ARNT表达的瞬时增加可以促进AHR稳定并积累到核区室中。较高的核AHR含量可能有利于AHR-ARNT异二聚体，该异源二聚体能够与异种素响应元件结合并在没有异种素的情况下诱导基因转录。因此，取决于细胞环境，生理调节的蛋白酶体活性可以参与内源性AHR功能的控制。

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