2012年1月10日,，國(guó)際學(xué)術(shù)期刊Journal of Cell Science發(fā)表了同濟(jì)大學(xué)醫(yī)學(xué)院徐國(guó)彤教授課題組的研究論文 “Binding of the ERa and ARNT1 AF2 domains to exon 21 of the SRC1 isoform SRC1e is essential for estrogen and dioxin-related transcription ",。
該論文發(fā)現(xiàn)雌激素受體和芳香烴受體核轉(zhuǎn)位蛋白1（ARNT1）上的活性域2的結(jié)合點(diǎn)在類固醇受體共激活因子1（SRC 1）的C-端上，證明了此結(jié)合在哺乳動(dòng)物細(xì)胞中可以上調(diào)由于雌激素和二惡英引起的相關(guān)反應(yīng)活性,。SRC1是涉及核受體的許多轉(zhuǎn)錄因子的轉(zhuǎn)錄共激活因子,。ARNT1是芳香烴受體和缺氧誘導(dǎo)因子-1a（HIF-1a）轉(zhuǎn)錄時(shí)必須的伙伴因子，也是一個(gè)雌激素受體的共激活因子,。
本研究中,，研究員Endler博士及其同事發(fā)現(xiàn)，轉(zhuǎn)錄啟動(dòng)時(shí)受雌激素激活的雌激素受體的活性域2(AF2)與SRC 1上的核受體相互作用域（NID）上的LxxLL區(qū)域發(fā)生作用,。雌激素和不受AF2作用的 LxxLL域可以作用于SRC 1的外顯子21,；另外， ARNT1的外顯子16可以與SRC 1的外顯子21相結(jié)合,。有意思的是,， SRC 1的外顯子21和AF2的結(jié)合可以成為雌激素誘導(dǎo)的重要的轉(zhuǎn)錄增強(qiáng)子。ARNT1上的活性域2與SRC 1的外顯子21結(jié)合可以增強(qiáng)對(duì)二惡英的轉(zhuǎn)錄反應(yīng),，但是此上調(diào)反應(yīng)基本上取決于兩個(gè)細(xì)胞周期破壞盒（D-盒）,，而此D-盒正好位于ARNT1的第16個(gè)外顯子。
該研究項(xiàng)目得到了科技部,、國(guó)家自然科學(xué)基金委,、上海市科委和中國(guó)科學(xué)院的資助。(生物谷 Bioon.com)
doi:10.1242/jcs.097246
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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.
