文章：

雌激素受体激活和蛋白水解之间的联系：与激素调节的癌症治疗相关

Links between oestrogen receptor activation and proteolysis: relevance to hormone-regulated cancer therapy

原文发布日期：2013-12-23

DOI: 10.1038/nrc3622

类型: Review Article

开放获取: 否

要点：

1. When oestrogen binds to the oestrogen receptor (ER), the ER dimerizes and translocates into the nucleus, where it recruits co-activators or co-repressors, as well as chromatin-remodelling factors, to oestrogen response elements (EREs) on target gene promoters in order to activate or repress transcription.
2. Multiple signalling pathways downstream of receptor tyrosine kinases (such as ERBB2, epidermal growth factor receptor 1 and insulin-like growth factor 1 receptor) coordinately regulate the dynamics of ER-mediated transcriptional regulation.
3. The availability of ER co-activators and ER co-repressors and their post-translational modifications determine the selectivity and timing of target gene expression. Many ER co-activators have enzymatic activities, including acetylation, methylation, demethylation and phosphorylation.
4. Several ER co-activators also regulate ubiquitin-dependent proteolysis and modify ER. For example, MAPK mediates ER phosphorylation at S294 and cyclin E–cyclin-dependent kinase 2 (CDK2) phosphorylates ER at S341 to prime the interaction of ER with S-phase kinase-associated protein 2, which is the substrate- recognition subunit of the SKP1–cullin 1–F-box protein ubiquitin ligase complex. This drives target gene transcription and mediates ubiquitin-dependent ER proteolysis.
5. These findings provide considerable insight into the subtleties of hormone-regulated steroid receptor stability and function that could ultimately lead to novel therapeutic strategies based on the manipulation of hormone receptor stability.

要点翻译：

1. 当雌激素与雌激素受体（ER）结合后，ER会发生二聚化并转移至细胞核，在靶基因启动子的雌激素反应元件上招募共激活因子或共抑制因子以及染色质重塑因子，从而激活或抑制转录过程。
2. 受体酪氨酸激酶下游的多种信号通路（如ERBB2、表皮生长因子受体1和胰岛素样生长因子1受体）协同调节ER介导的转录调控动态。
3. ER共激活因子和ER共抑制因子的可用性及其翻译后修饰决定了靶基因表达的选择性和时序性。许多ER共激活因子具有酶活性，包括乙酰化、甲基化、去甲基化和磷酸化作用。
4. 部分ER共激活因子还调控泛素依赖性蛋白降解并修饰ER。例如，MAPK介导ER的S294位点磷酸化，细胞周期蛋白E-周期蛋白依赖性激酶2（CDK2）则磷酸化ER的S341位点，以此启动ER与S期激酶相关蛋白2的相互作用——后者是SKP1-Cullin1-F-box蛋白泛素连接酶复合物的底物识别亚基。这一机制驱动靶基因转录并介导泛素依赖性的ER蛋白降解。
5. 这些发现深刻揭示了激素调节类固醇受体稳定性与功能的精妙机制，最终可能为基于激素受体稳定性调控的新型治疗策略奠定基础。

英文摘要：

Oestrogen receptor-α (ERα) is a master transcription factor that regulates cell proliferation and homeostasis in many tissues. Despite beneficial ERα functions, sustained oestrogenic exposure increases the risk and/or the progression of various cancers, including those of the breast, endometrium and ovary. Oestrogen–ERα interaction can trigger post-translational ERα modifications through crosstalk with signalling pathways to promote transcriptional activation and ubiquitin-mediated ERα proteolysis, with co-activators that have dual roles as ubiquitin ligases. These processes are reviewed herein. The elucidation of mechanisms whereby oestrogen drives both ERα transactivation and receptor proteolysis might have important therapeutic implications not only for breast cancer but also potentially for other hormone-regulated cancers.

摘要翻译： 

雌激素受体-α（ERα）是一种主转录因子，可调节多种组织的细胞增殖和稳态。尽管ERα功能有益，但持续的雌激素暴露会增加多种癌症（包括乳腺、子宫内膜和卵巢癌）的风险和/或进展。雌激素-ERα相互作用可通过与信号通路的串扰触发ERα翻译后修饰，以促进转录激活和泛素介导的ERα蛋白降解，其中共激活因子扮演双重角色，即泛素连接酶。本文对这些过程进行了综述。阐明雌激素驱动ERα转录激活和受体蛋白降解的机制，可能对乳腺癌以及其他激素调节的癌症具有重要的治疗意义。

原文链接：

Links between oestrogen receptor activation and proteolysis: relevance to hormone-regulated cancer therapy