A direct β-catenin-independent interaction between androgen receptor and T cell factor 4
A direct β-catenin-independent interaction between androgen receptor and T cell factor 4
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DOI：
10.1074/jbc.m301208200
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发表时间：
2003-08-15
影响因子：
4.8
通讯作者：
Balk, SP
中科院分区：
文献类型：
--
作者：
Amir, AL;Barua, M;Balk, SP
T细胞因子（Tcf）蛋白结合β-连环蛋白并且是Wnt/β-连环蛋白信号的下游效应物。最近证实的β-连环蛋白和雄激素受体（AR）配体结合结构域之间的相互作用表明，AR可能是一个Tcf-独立的Wnt/β-连环蛋白效应。这项研究表明，AR DNA结合结构域（DBD）和Tcf 4之间存在直接相互作用。Tcf 4特异性结合谷胱甘肽S-转移酶-ARDBD融合蛋白，并可与β-连环蛋白和前列腺癌细胞中转染的AR或内源性AR共免疫沉淀。转染的Tcf 4抑制全长AR和VP 16-ARDBD融合蛋白的转录活性，并且这种抑制仅被转染的β-连环蛋白部分逆转。醋酸环丙孕酮（一种不支持β-连环蛋白与AR结合的部分激动剂）的AR激活也被Tcf 4抑制，进一步表明抑制不是由于β-连环蛋白螯合。Tcf 4可以在体外将β-连环蛋白募集到AR DBD，并在体内将β-连环蛋白募集到环丙孕酮配体的AR。LNCaP前列腺癌细胞中的染色质免疫沉淀实验表明，内源性AR与c-myc启动子中的Tcf 4响应元件结合。这些发现表明AR和Tcf 4可以直接相互作用，并且这种相互作用可能发生在特定基因的启动子或增强子上。直接的AR-Tcf 4相互作用，结合AR-和Tcf 4-β-连环蛋白结合，提供了一种通过AR和Wnt/β-连环蛋白-Tcf途径进行合作和选择性基因调控的机制，可能有助于正常和肿瘤性前列腺生长。
T cell factor (Tcf) proteins bind beta-catenin and are downstream effectors of Wnt/beta-catenin signals. A recently demonstrated interaction between beta-catenin and the androgen receptor (AR) ligand binding domain has suggested that AR may be a Tcf-independent Wnt/beta-catenin effector. This study demonstrates that there is a direct interaction between the AR DNA binding domain (DBD) and Tcf4. Tcf4 bound specifically to a glutathione S-transferase-ARDBD fusion protein and could be coimmunoprecipitated with beta-catenin and transfected AR or endogenous AR in prostate cancer cells. Transfected Tcf4 repressed the transcriptional activity of full-length AR and a VP16-ARDBD fusion protein, and this repression was only partially reversed by transfected beta-catenin. AR activation by cyproterone acetate, a partial agonist that did not support beta-catenin binding to the AR, was also repressed by Tcf4, further indicating that repression was not due to beta-catenin sequestration. Tcf4 could recruit beta-catenin to the AR DBD in vitro and to the cyproterone acetate-liganded AR in vivo. Chromatin immunoprecipitation experiments in LNCaP prostate cancer cells showed that endogenous AR was bound to a Tcf4-responsive element in the c-myc promoter. These findings indicate that AR and Tcf4 can interact directly and that this interaction may occur on the promoters or enhancers of particular genes. The direct AR-Tcf4 interaction, in conjunction AR- and Tcf4-beta-catenin binding, provides a mechanism for cooperative and selective gene regulation by AR and the Wnt/beta-catenin-Tcf pathway that may contribute to normal and neoplastic prostate growth.