Cross-talk between ERs and signal transducer and activator of transcription 5 is E2 dependent and involves two functionally separate mechanisms
Cross-talk between ERs and signal transducer and activator of transcription 5 is E2 dependent and involves two functionally separate mechanisms
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DOI：
10.1210/me.15.11.1929
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发表时间：
2001-11-01
影响因子：
--
通讯作者：
Haldosén, LA
中科院分区：
文献类型：
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作者：
Faulds, MH;Pettersson, K;Haldosén, LA
类固醇激素受体和信号转导及转录激活子(STAT)因子组成了两个不同的转录因子家族，它们由不同的信号通路激活。在以前的报告中，STAT5和几个类固醇受体之间的串扰已经被证明。我们研究了ERα、ERβ和STAT5之间可能的串扰。ERα和ERβ被发现以配体依赖的方式有效地抑制含有PRL的STAT5在β-酪蛋白启动子结构上的转录活性。这种下调依赖于ERs和STAT5之间的直接物理相互作用，这种相互作用是通过ER DNA结合域(DBD)介导的。ER DBD和STAT5之间的接触具有高度的特异性；如果Era DBD被密切相关的类固醇受体的DBD取代，这种相互作用就会取消。然而，物理相互作用不足以抑制STAT5的活性，此外，这还需要ELL的配体激活的C末端部分，尽管这些结构域不与STAT5直接接触。因此，ERs和STAT5之间的负干扰是通过ERs的几个功能分离的结构域来调节的。我们的发现可能会加强对不同激素信号通路的调节机制的理解，这些信号通路发生在共表达ER和STAT5的组织中的不同功能事件中。
Steroid hormone receptors and signal transducers and activators of transcription (STAT) factors constitute two distinct families of transcription factors activated by different signaling pathways. In previous reports, cross-talk between STAT5 and several steroid receptors has been demonstrated. We investigated putative cross-talk between ER alpha and ER beta and STAT5. ER alpha and ER beta were found to potently repress PRL-incluced STAT5 transcriptional activity on a beta -casein promoter construct in a ligand-dependent manner. This down-regulation was found to rely on direct physical interaction between the ERs and STAT5, mediated via the ER DNA-binding domain (DBD). The contact between the ER DBD and STAT5 is highly specific; the interaction is abolished if the ERa DBD is replaced with the DBD of a closely related steroid receptor. The physical interaction, however, is insufficient to confer the repression of STAT5 activity, which in addition requires the ligand-activated C-terminal part of the Ells, although these domains are not in direct contact with STAT5. Negative cross-talk between ERs and STAT5 is thus mediated via several functionally separated domains of the ERs. Our findings may enhance the understanding of mechanisms of regulation of the different hormonal signaling pathways occurring during different functional events in tissues coexpressing ERs and STAT5.