Aryl hydrocarbon receptor-mediated antiestrogenicity in MCF-7 cells: modulation of hormone-induced cell cycle enzymes.
Aryl hydrocarbon receptor-mediated antiestrogenicity in MCF-7 cells: modulation of hormone-induced cell cycle enzymes.
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DOI：
10.1006/abbi.1998.0782
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发表时间：
1998-08
影响因子：
3.9
通讯作者：
Weili Wang;R. Smith;S. Safe
中科院分区：
文献类型：
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作者：
Weili Wang;R. Smith;S. Safe
2，3，7，8-四氯二苯并-对-二恶英（TCDD）抑制啮齿动物和MCF-7人类乳腺癌细胞中17 β-雌二醇（E2）乳腺肿瘤的生长;然而，尚未确定受抑制的细胞周期基因/蛋白质。初步研究表明，用10 nM E2处理MCF-7细胞可显著增加细胞周期蛋白D1（蛋白和mRNA）、cdk 2和cdk 4依赖性激酶活性以及视网膜母细胞瘤（RB）蛋白的过度磷酸化。与最近的研究结果相反（M。D. Planas-Silva和R. A.温伯格，1997年，Mol. Cell. 17，4059-4069），E2诱导cdk 2和cdk 4蛋白从p21蛋白复合物解离，并显著增加cdk 7依赖性激酶活性。用E2处理MCF-7细胞也诱导cdc 25 A磷酸酶蛋白，其伴随着含有未磷酸化酪氨酸残基的cdk 2和cdk 4蛋白的增加。虽然TCDD单独对细胞周期蛋白/酶的影响很小，但在MCF-7细胞中，几种E2诱导的反应被E2加TCDD共处理显著抑制。例如，TCDD显着抑制E2诱导的RB，细胞周期蛋白D1蛋白和cdk 2，cdk 4和cdk 7依赖性激酶活性的过度磷酸化。TCDD对E2诱导的cdk 4依赖性激酶活性的抑制可能与E2诱导的cyclin D1蛋白的平行减少有关，而对诱导的cdk 2和cdk 4依赖性激酶活性的抑制可能是由于TCDD + E2共处理细胞中p21水平的显著增加。这些结果表明，TCDD的抗雌激素活性是由于下调了几个E2诱导的细胞周期蛋白/活动，这说明了芳烃和E2受体信号传导途径之间的复杂的串扰。
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) inhibits 17beta-estradiol (E2) mammary tumor growth in rodents and in MCF-7 human breast cancer cells; however, the cell cycle genes/proteins which are inhibited have not been determined. Initial studies showed that treatment of MCF-7 cells with 10 nM E2 significantly increased cyclin D1 (protein and mRNA), cdk2- and cdk4-dependent kinase activities, and hyperphosphorylation of retinoblastoma (RB) protein. In contrast to results of recent studies (M. D. Planas-Silva and R. A. Weinberg, 1997, Mol. Cell. Biol. 17, 4059-4069), E2 induced dissociation of both cdk2 and cdk4 proteins from the p21 protein complex and significantly increased cdk7-dependent kinase activity. Treatment of MCF-7 cells with E2 also induced cdc25A phosphatase protein, which was accompanied by increased cdk2 and cdk4 proteins containing unphosphorylated tyrosine residues. Although TCDD alone has minimal effects on cell cycle proteins/enzymes, several E2-induced responses were significantly inhibited in MCF-7 cells cotreated with E2 plus TCDD. For example, TCDD significantly inhibited E2-induced hyperphosphorylation of RB, cyclin D1 protein, and cdk2-, cdk4-, and cdk7-dependent kinase activities. Inhibition of E2-induced cdk4-dependent kinase activity by TCDD may be related to the parallel decrease of E2-induced cyclin D1 protein, and inhibition of induced cdk2- and cdk4-dependent kinase activities may be due to significantly increased p21 levels in cells cotreated with TCDD plus E2. These results demonstrate that the antiestrogenic activity of TCDD is due to downregulation of several E2-induced cell cycle proteins/activities and this illustrates the complex cross talk between the aryl hydrocarbon and the E2 receptor signaling pathways.