Study on clarification of unregulated gene expression to genome network by dioxin and related compounds using a human alveolar carcinoma cell line

使用人肺泡癌细胞系阐明二恶英及相关化合物对基因组网络不受调控的基因表达的研究

• 批准号: 13672351
• 负责人: TEZUKA Masakatsu
• 金额: $ 2.24万
• 依托单位: Nihon University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13672351/
• 关键词: A549 cells; AhR; E2F; DP2; ダイオキシン類; CDK4; PCNA; MM-1; CDC10-like

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 (dioxin) 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.In this study, we first investigated the role of AhR on cell proliferation. The cell proliferation of A549 cells, a human alveolar carcinoma cell line, was enhanced by the treatment with the AhR-ligand, β -naphthoflavone. The enhancement effect was disappeared by the co-treatment with the AhR-antagonist, α-naphthoflavone. Next, in order 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 t … More he 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. 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. Less

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-p-二恶英（二恶英）和相关化合物的一系列毒性和生物学效应。虽然AhR的生理配体还没有被确定，一些报告表明，AhR可能发挥重要作用，不仅在调节外源性物质的代谢，而且在维持稳态的functions.In本研究中，我们首先研究了AhR对细胞增殖的作用。用AhR配体β -萘甲酮处理人肺泡癌细胞系A549，可促进细胞增殖。与AhR拮抗剂α-萘甲酮共同处理后，这种增强效应消失。接下来，为了获得AhR调节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更快，并且生长速率与t成正比。 ...更多信息 AhR的数量。细胞周期分析表明，AhR的过度表达的细胞生长的加速是最有可能是由于后期M到S期缩短。对细胞周期调节因子表达谱的研究表明，AhR或AhR配体诱导DP 2、PCNA和RFC 38的表达。DP 2是与E2 F形成功能性二聚体并调节参与DNA合成的几个基因的表达的转录因子。有趣的是，PCNA和RFC 38都是E2 F和DP复合物的靶基因。E2 F活性在AhR过表达细胞和AhR激动剂处理的细胞中均显著增加，表明AhR激活的E2 F/DP 2可诱导PCNA和RFC 38的表达以及随后的DNA合成。通过RNAi下调Arnt的表达，减弱了AhR对A549细胞增殖的影响。因此，我们得出结论，AhR，大概与Arnt合作，激活A549细胞中的DNA合成和随后的细胞增殖。少

项目成果

S. Shimba, M. Tezuka et al.: "Overexpression of the Aryl Hydrocarbon Receptor (AhR) Accelerates the Cell Proliferation of A549 Cells"J. Biochem.. 132. 795-802 (2002)

S. Shimba、M. Tezuka 等人：“芳基烃受体 (AhR) 的过度表达加速 A549 细胞的细胞增殖”J.

S.Shimba, M.Tezuka et al.: "Overexpression of the Aryl Hydrocarbon Receptor (AhR) Accelerates the Cell Proliferation of A549 Cells"Journal of Biochemistry. 132. 795-802 (2002)

S.Shimba、M.Tezuka 等人：“芳基烃受体 (AhR) 的过度表达加速 A549 细胞的细胞增殖”生物化学杂志。