Inhibition of estrogen receptor activity by the tumor promoter 12-O-tetradeconylphorbol-13-acetate: a molecular analysis.
Inhibition of estrogen receptor activity by the tumor promoter 12-O-tetradeconylphorbol-13-acetate: a molecular analysis.
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DOI：
10.1210/mend-5-12-1983
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发表时间：
1991-12
影响因子：
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通讯作者：
M. Tzukerman;Xiao‐kun Zhang;Magnus Pfahl
中科院分区：
文献类型：
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作者：
M. Tzukerman;Xiao‐kun Zhang;Magnus Pfahl
雌性生殖组织的细胞增殖和表型受雌激素的调节。因此，重要的是要了解雌激素的作用是如何被调节的。最近有报道，某些核受体可以通过与转录因子AP-1直接相互作用来拮抗肿瘤促进剂12-O-十四烷基佛波醇-13-乙酸酯(TPA)，并且AP-1成分cJun和CFos可以抑制受体的活性。这种相互对抗似乎是建立在蛋白质与蛋白质直接相互作用的基础上的。在人乳腺癌细胞系MCF-7中，TPA导致生长停滞和细胞形态改变。我们在这里研究了在MCF-7细胞和其他细胞系中，AP-1和雌激素受体(ER)是否可以相互抑制活性。我们发现，在所研究的大多数细胞系中，TPA或AP-1成分cJun和CFos可以抑制雌激素依赖性雌激素受体的活性。此外，在MCF-7细胞中，ER基因的表达迅速下调。凝胶滞留实验表明，cJun蛋白在体外对ER DNA结合有抑制作用，而ER也能抑制cJun DNA结合。然而，在体内，我们没有观察到内质网对AP-1活性的抑制。相反，我们观察到低浓度的内质网对AP-1有促进作用。综上所述，我们的数据提示了一条新的调控途径，通过该途径，AP-1可以调节ER的活性。包括ER-AP-1蛋白相互作用在内的几种机制似乎参与了这一过程。
Cell proliferation and phenotype of cells from female reproductive tissues are regulated by estrogens. It is therefore important to understand how estrogen action can be modulated. It recently has been reported that certain nuclear receptors can antagonize the tumor promoter 12-O-tetradeconylphorbol-13-acetate (TPA) by direct interaction with the transcription factor AP-1, and that the AP-1 constituents cJun and cFos can inhibit receptor activity. This mutual antagonism appears to be based on direct protein-protein interaction. In the human breast cancer cell line MCF-7, TPA leads to growth arrest and altered cell morphology. We have investigated here whether in MCF-7 cells and other cell lines AP-1 and estrogen receptors (ERs) can inhibit each other's activity. We find that TPA or the AP-1 components cJun and cFos can inhibit estradiol-dependent estrogen receptor activity in most cell lines investigated. In addition, ER mRNA is rapidly down-regulated in MCF-7 cells. Gel retardation experiments show that ER DNA binding is inhibited in vitro by cJun protein, while ER also can inhibit cJun DNA binding. However, in vivo we do not observe inhibition of AP-1 activity by ER in the cell lines investigated here. On the contrary, we observed an enhancing effect at low ER concentrations on AP-1. Together our data suggest a new regulatory pathway by which ER activity can be modulated by AP-1. Several mechanisms including ER-AP-1 protein interaction appear to be involved.