2012年1月10日，国际学术期刊Journal of Cell Science发表了同济大学医学院徐国彤教授课题组的研究论文 “Binding of the ERa and ARNT1 AF2 domains to exon 21 of the SRC1 isoform SRC1e is essential for estrogen and dioxin-related transcription "。
该论文发现雌激素受体和芳香烃受体核转位蛋白1（ARNT1）上的活性域2的结合点在类固醇受体共激活因子1（SRC 1）的C-端上，证明了此结合在哺乳动物细胞中可以上调由于雌激素和二恶英引起的相关反应活性。SRC1是涉及核受体的许多转录因子的转录共激活因子。ARNT1是芳香烃受体和缺氧诱导因子-1a（HIF-1a）转录时必须的伙伴因子，也是一个雌激素受体的共激活因子。
本研究中，研究员Endler博士及其同事发现，转录启动时受雌激素激活的雌激素受体的活性域2(AF2)与SRC 1上的核受体相互作用域（NID）上的LxxLL区域发生作用。雌激素和不受AF2作用的 LxxLL域可以作用于SRC 1的外显子21；另外， ARNT1的外显子16可以与SRC 1的外显子21相结合。有意思的是， SRC 1的外显子21和AF2的结合可以成为雌激素诱导的重要的转录增强子。ARNT1上的活性域2与SRC 1的外显子21结合可以增强对二恶英的转录反应，但是此上调反应基本上取决于两个细胞周期破坏盒（D-盒），而此D-盒正好位于ARNT1的第16个外显子。
该研究项目得到了科技部、国家自然科学基金委、上海市科委和中国科学院的资助。(生物谷 Bioon.com)
doi:10.1242/jcs.097246
PMC:
PMID:
Binding of the ERα and ARNT1 AF2 domains to exon 21 of the SRC1 isoform SRC1e is essential for estrogen- and dioxin-related transcription.
Alexander Endler, Li Chen, Jun Zhang, Guo-Tong Xu andFutoshi Shibasaki
Steroid receptor co-activator 1 (SRC1) is a transcriptional co-activator of numerous transcription factors involving nuclear receptors. Aryl hydrocarbon receptor nuclear translocator 1 (ARNT1) is an obligatory transcriptional partner of the aryl hydrocarbon receptor (AhR) and hypoxia inducible factor-1α (HIF-1α), as well as a co-activator of estrogen receptors (ERs). To initiate transcription, the activation function 2 (AF2) domains of estrogen-activated ERs interact with LxxLL motifs in the nuclear receptor interaction domain (NID) of SRC1. Here we describe an estrogen and LxxLL domain-independent ERα AF2 binding to SRC1e exon 21. In addition, we found an AF2 domain in exon 16 of ARNT1 that also binds to SRC1e exon 21. Surprisingly, the interaction between SRC1e exon 21 and the AF2 domain of ERα functions as a crucial enhancer of estrogen-induced transcription. The binding of ARNT1 AF2 to SRC1e exon 21 enhances the transcriptional response to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), but the upregulation essentially depends on two cyclin destruction boxes (D-boxes), which are also located on exon 16 of ARNT1. Our findings reveal that a binding site for ERα and ARNT1 AF2 domains in the C-terminus of SRC1e upregulates estrogen- and TCDD-related responses in mammalian cells.
