Aryl Hydrocarbon Receptor and Stem Cells.
Aryl Hydrocarbon Receptor and Stem Cells.
复制标题
芳基烃受体和干细胞。
DOI：
10.1155/2017/4602854
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发表时间：
2017
影响因子：
4.3
通讯作者：
Casado,FannyL
中科院分区：
文献类型：
--
作者：
Gasiewicz,ThomasA;Singh,KameshwarP;Casado,FannyL
从生化角度来看，芳烃受体（AHR）是 bHLH/PAS 转录因子家族中高度保守、发育调节且配体激活的成员。 AHR 最初被发现是因为其最有效和持久的配体 2,3,7,8-四氯二苯并-二恶英（通常简称为“二恶英”）对人类和动物具有毒性。对 AHR 的规范理解表明，它作为多蛋白复合物的组成部分之一存在于胞质溶胶中，该多蛋白复合物包含亲免素样蛋白 XAP2/AIP/ARA9、23 kDa 共伴侣蛋白 p23 和两个 HSP90 分子。配体结合后，它易位到细胞核，与 HIF-1beta 又名 ARNT 形成异二聚体，它们一起可以激活基因转录。后来的研究表明，二恶英还可以作为内分泌干扰物[1]和具有促肿瘤特性的致癌物质，并在化学诱导的癌变起始、进展和转移过程中间接发挥作用。流行病学研究表明，人类接触环境 AHR 配体与多种癌症 [2] 以及糖尿病和肥胖症发病率增加有关 [3]。虽然最近的研究集中在可能在患病组织或活跃的先天性和适应性免疫中表达的生理相关的 AHR 配体上，但直到研究表明与各种来源组织的干细胞存在联系之前，没有充分认识到没有配体结合的 AHR 的生理相关性[4]。此外，当 Boitano 等人[5]时，AHR 完全脱离了毒理学研究的专业领域。通过促进体外造血干细胞的扩增，显示了受体的药理学潜力。在本期特刊中，提出了原始报告和全面的评论，讨论了组织提供的不同背景，并使干细胞中的 AHR 易于对不同的刺激（如配体结合和氧化应激）做出反应。此外，很明显，当前的生物技术方法正在提供对多种细胞类型中 AHR 行为的更全面的了解，这得益于基因组编辑工具，现在成为可能。随着世界范围内多卤农药的使用禁止和香烟烟雾暴露的减少，AHR 研究引导人们努力更深入地了解干细胞操作时代毒性的含义。
From the biochemical point of view, the aryl hydrocarbon receptor (AHR) is a highly conserved, developmentally regulated, and ligand-activated member of the bHLH/PAS family of transcription factors. The AHR was originally discovered because of the human and animal toxicity of its most potent and persistent ligand, 2, 3, 7, 8-tetrachlorodibenzo-pdioxin, usually just referred to as “dioxin.” The canonical understanding of the AHR indicates that it is present in the cytosol as one of the components of a multiprotein complex containing the immunophilin-like protein XAP2/AIP/ARA9, the 23 kDa cochaperone protein p23, and two molecules of HSP90. After ligand binding, it translocates to the nucleus forming a heterodimer with HIF-1beta aka ARNT and together they can activate gene transcription. Later studies demonstrated that dioxins also act as endocrine disruptors [1] and as carcinogens with tumorpromoting properties and indirect roles in chemically induced carcinogenesis during initiation, progression, and metastasis. Epidemiological studies linked human exposure to environmental AHR ligands to increased incidence of diverse cancers [2], as well as diabetes and obesity [3]. While more recent research has focused on the physiologically relevant AHR ligands which might be expressed in diseased tissues or active innate and adaptive immune, the physiological relevance of the AHR without ligand binding was not fully appreciated until studies showed a link with stem cells of various tissues of origin [4]. Furthermore, AHR completely left the specialized realm of toxicological research when Boitano et al.[5] showed the pharmacological potential of the receptor by promoting expansion of hematopoietic stem cells in vitro.In this special issue, original reports as well as thorough reviews are presented addressing the different contexts provided by the tissues and making AHR in stem cells prone to respond to different stimuli such as ligand binding and oxidative stress. Also, it is evident that current biotechnological approaches are providing a more comprehensive understanding of AHR behavior in multiple cell types which is now possible thanks to genome editing tools. With worldwide banning of polyhalogenated pesticides usage and decreases in cigarette-smoke exposures, AHR research leads the efforts to a more sophisticated understanding about the meanings of toxicity in an era of stem cell manipulation.