Down-Regulation of p23 in Normal Lung Epithelial Cells Reduces Toxicities From Exposure to Benzo[a]pyrene and Cigarette Smoke Condensate via an Aryl Hydrocarbon Receptor-Dependent Mechanism
Down-Regulation of p23 in Normal Lung Epithelial Cells Reduces Toxicities From Exposure to Benzo[a]pyrene and Cigarette Smoke Condensate via an Aryl Hydrocarbon Receptor-Dependent Mechanism
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DOI：
10.1093/toxsci/kfy234
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发表时间：
2019-01-01
影响因子：
3.8
通讯作者：
Chan, William K.
中科院分区：
文献类型：
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作者：
Chen, Jinyun;Yakkundi, Poonam;Chan, William K.
芳烃受体（AHR）是一种配体激活的信号分子，控制肿瘤的生长和转移、T细胞的分化和肝脏的发育。该受体蛋白的表达水平对细胞p23蛋白水平敏感。只要减少30%的p23细胞含量就能抑制AHR功能。在这里，我们报道了在正常的、未转化的人支气管/气管上皮细胞中，p23蛋白含量下调至其含量的48%，也会抑制AHR蛋白水平至其含量的54%。这种p23介导的AHR抑制负责抑制(1)cyp1a1基因转录的配体依赖性诱导；(2)苯并[a]芘或香烟烟雾冷凝物诱导CYP1A1酶活性，(3)苯并[a]芘和香烟烟雾冷凝物介导活性氧的产生。p23含量的降低不会改变氧化应激基因的表达和PGE的产生(2)。p23的下调抑制了另外两种未转化细胞类型的AHR蛋白水平，即人乳腺MCF-10A和小鼠免疫调节Tr1细胞。总的来说，p23的下调抑制了正常细胞和未转化细胞中的AHR蛋白水平，原则上可以保护我们的肺上皮细胞免受由暴露于环境和吸烟引起的AHR依赖性氧化损伤。
The aryl hydrocarbon receptor (AHR) is a ligand-activated signaling molecule which controls tumor growth and metastasis, T cell differentiation, and liver development. Expression levels of this receptor protein is sensitive to the cellular p23 protein levels in immortalized cancer cell lines. As little as 30% reduction of the p23 cellular content can suppress the AHR function. Here we reported that down-regulation of the p23 protein content in normal, untransformed human bronchial/tracheal epithelial cells to 48% of its content also suppresses the AHR protein levels to 54% of its content. This p23-mediated suppression of AHR is responsible for the suppression of (1) the ligand-dependent induction of the cyp1a1 gene transcription; (2) the benzo[a]pyrene- or cigarette smoke condensate-induced CYP1A1 enzyme activity, and (3) the benzo[a]pyrene and cigarette smoke condensate-mediated production of reactive oxygen species. Reduction of the p23 content does not alter expression of oxidative stress genes and production of PGE(2). Down regulation of p23 suppresses the AHR protein levels in two other untransformed cell types, namely human breast MCF-10A and mouse immune regulatory Tr1 cells. Collectively, down-regulation of p23 suppresses the AHR protein levels in normal and untransformed cells and can in principle protect our lung epithelial cells from AHR-dependent oxidative damage caused by exposure to agents from environment and cigarette smoking.