Overexpression of the aryl hydrocarbon receptor (AhR) accelerates the cell proliferation of A549 cells
Overexpression of the aryl hydrocarbon receptor (AhR) accelerates the cell proliferation of A549 cells
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DOI：
10.1093/oxfordjournals.jbchem.a003289
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发表时间：
2002-11-01
影响因子：
2.7
通讯作者：
Tezuka, M
中科院分区：
文献类型：
--
作者：
Shimba, S;Komiyama, K;Tezuka, M
芳烃受体（AhR）是一种配体激活的转录因子，介导2,3,7,8-四氯二苯并-对二恶英（TCDD）及其相关化合物的一系列毒性和生物学效应。虽然AhR的生理配体尚未确定，但一些报道表明，AhR可能不仅在调节异种代谢方面发挥重要作用，而且在维持体内平衡功能方面也发挥重要作用[Singh等人（1996）]。物化学。中国生物医学工程学报（英文版）；Crawford et al. (1997) Mol. Pharmacol. 52, 921-927；Chang et al. (1998) Mol. Cell。[j].中国生物医学工程学报，2004,18(5):525-535。一些证据表明，AhR的一个可能的生理作用是调节细胞增殖。在这项研究中，我们首次发现用AhR激动剂处理A549细胞可以刺激细胞增殖。与α -萘黄酮共处理可拮抗该效应。为了获得AhR调控细胞增殖的直接证据，我们分离了过表达AhR的克隆。这些克隆比对照细胞生长得快，生长速度与AhR的量成正比。细胞周期分析显示，过表达AhR加速细胞生长很可能是由于缩短了M期晚期到S期。对细胞周期调节因子表达谱的研究表明，AhR或AhR配体可诱导DP2、PCNA和RFC38的表达。DP2是与E2F形成功能性二聚体的转录因子，并调控几个参与DNA合成的基因的表达。有趣的是，PCNA和RFC38都是E2F和DP复合物的靶基因。此外，这两个因子都参与调节DNA聚合酶的活性。在过表达ahr的细胞和ahr激动剂处理的细胞中，E2F活性均显著增加，这表明ahr激活的E2F/DP2可能诱导PCNA和RFC38的表达以及随后的DNA合成。RNAi下调Arnt的表达可减弱AhR对A549细胞增殖的影响。因此，我们得出结论，AhR可能与Arnt合作，激活了A549细胞的DNA合成和随后的细胞增殖。
The arylhydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates a spectrum of toxic and biological effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds. Although the physiological ligand for the AhR has not yet been identified, several reports have suggested that the AhR may play important roles not only in the regulation of xenobiotic metabolism but also in the maintenance of homeostatic functions [Singh et al. (1996) Arch. Biochem. Biophys. 329, 47-55; Crawford et al. (1997) Mol. Pharmacol. 52, 921-927; Chang et al. (1998) Mol. Cell. Biol. 18, 525-535]. Several lines of evidence suggest that one of the possible physiological roles of the AhR is regulation of cell proliferation. In this study, we first showed that treatment of A549 cells with the AhR agonist stimulates cell proliferation. The effect was antagonized by co-treatment with alpha-naphthoflavone. To obtain direct evidence that the AhR regulates cell proliferation, we isolated the clones that overexpress the AhR. These clones grow faster than control cells, and the rate of growth is proportional to the amount of the AhR. Cell cycle analysis revealed that the acceleration of cell growth by overexpression of the AhR is most probably due to shortening of the late M to S phases. Studies on the expression profiles of cell cycle regulators showed that the AhR or AhR ligand induces the expression of DP2, PCNA, and RFC38. DP2 is the transcription factor that forms the functional dimer with E2F and regulates the expression of several genes involved in DNA synthesis. Interestingly, both PCNA and RFC38 are target genes of E2F and the DP complex. Also, both of these factors are involved in regulating DNA polymerase delta activity. E2F activity was substantially increased in both the AhR-overexpressing cells and the AhR-agonist treated cells, suggesting that AhR-activated E2F/DP2 may induce the expression of PCNA and RFC38 and subsequent DNA synthesis. Down-regulation of the expression of the Arnt by RNAi diminished the effects of the AhR on the cell proliferation of the A549 cells. Consequently, we conclude that the AhR, presumably in collaboration with the Arnt, activates the DNA synthesis and the subsequent cell proliferation in A549 cells.