Differential modulation of transcriptional activity of estrogen receptors by direct protein-protein interactions with the T cell factor family of transcription factors
Differential modulation of transcriptional activity of estrogen receptors by direct protein-protein interactions with the T cell factor family of transcription factors
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DOI：
10.1074/jbc.m103966200
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发表时间：
2001-11-09
影响因子：
4.8
通讯作者：
Rudland, P
中科院分区：
文献类型：
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作者：
El-Tanani, M;Fernig, DG;Rudland, P
两个主要的信号通路，由雌激素（E-2）和Wnt家族触发，在乳腺中相互作用，导致生长和分化。雌激素受体ER α和ER β通过结合E-2而被激活，并作为配体依赖性转录因子发挥作用。Wnt家族的效应子是转录因子的Tcf家族。两组转录因子识别其靶基因启动子中离散但不同的核苷酸序列。通过在大鼠乳腺细胞中瞬时转染骨桥蛋白和胸苷激酶启动子的报告构建体，我们表明Tcf-4拮抗和Tcf-1刺激激活的ER/E-2的作用。对于前一种启动子的突变体，ER α/E-2的刺激作用可以依赖于Tcf-1，而对于后一种启动子，T细胞因子（TCF）的作用依赖于ER/E-2。ER和Tcfs之间的直接相互作用，无论是在Tcf/ER α结合位点的DNA或在DNA的情况下，建立凝胶阻滞试验或共免疫沉淀/生物传感器方法，分别。这些结果表明，这两组转录因子可以直接相互作用，ER与Tcf-4之间的相互作用是拮抗的，而ER与Tcf-1之间的相互作用是协同的。由于Tcf-4是乳腺中主要的Tcf家族成员，因此建议在该组织中，拮抗相互作用通常在体内占主导地位。
Two major signaling pathways, those triggered by estrogen (E-2) and by the Wnt family, interact in the breast to cause growth and differentiation. The estrogen receptors ERalpha and ERbeta are activated by binding E-2 and act as ligand-dependent transcription factors. The effector for the Wnt family is the Tcf family of transcription factors. Both sets of transcription factors recognize discrete but different nucleotide sequences in the promoters of their target genes. By using transient transfections of reporter constructs for the osteopontin and thymidine kinase promoters in rat mammary cells, we show that Tcf-4 antagonizes and Tcf-1 stimulates the effects of activated ER/E-2. For mutants of the former promoter, the stimulatory effects of ERalpha/E-2 can be made to be dependent on Tcf-1, and for the latter promoter the effects of the T cell factors (TCFs) are dependent on ER/E-2. Direct interaction between ERs and Tcfs either at the Tcf/ERalpha-binding site on the DNA or in the absence of DNA is established by gel retardation assays or by coimmuno-precipitation/biosensor methods, respectively. These results show that the two sets of transcription factors can interact directly, the interaction between ERs and Tcf-4 being antagonistic and that between ERs and Tcf-1 being synergistic on the activity of the promoters employed. Since Tcf-4 is the major Tcf family member in the breast, it is suggested that the antagonistic interaction is normally dominant in vivo in this tissue.