Estrogen receptor (ER), one member of nuclear hormone receptor (NR) family, is an estrogen-dependent transcriptional factor that plays an important role in development, progression and treatment of breast cancer. Tran...Estrogen receptor (ER), one member of nuclear hormone receptor (NR) family, is an estrogen-dependent transcriptional factor that plays an important role in development, progression and treatment of breast cancer. Transcriptional co-factors (co-activators and co-repressors) are critical for ER to transduce hormone and metabolic signaling to target genes. A number of functional and structural studies have elucidated the precise mechanisms of co-activator interaction with the ligand-inducible activation domain in ER via one and several LXXLL motifs (where X is any amino acid) known as NR-Box. By the yeast two-hybrid system we have identified a novel ER-a interacting protein ERIAP (Estrogen Receptor Interacting and Activating Protein) which contains two consensus LXXLL motifs. ERIAP associated with ER-a in a ligand-dependent manner, as demonstrated by in vivo immunoprecipitation and in vitro GST capture assays. The two NR boxes were essential for ERIAP interaction with ER-a. Furthermore, ERIAP specifically enhanced ligand-mediated ER-a transcriptional activity in a dose-dependent fasion and increased the expression of estrogen-responsive gene pS2. Thus, our present findings indicate that ERIAP funcions as a new coactivator for ER-a transcriptional activity, which may play an important role in development and progression of breast cancer.展开更多
雌激素受体(ER)属于核激素受体(NR)家族成员,是一种雌激素依赖性转录因子,在乳腺癌的发生、发展和治疗中起重要作用。协调转录因子(协调激活因子和协调抑制因子)在ER转导激素和代谢信号到靶基因时起着关键作用。功能和结构研究阐明,协...雌激素受体(ER)属于核激素受体(NR)家族成员,是一种雌激素依赖性转录因子,在乳腺癌的发生、发展和治疗中起重要作用。协调转录因子(协调激活因子和协调抑制因子)在ER转导激素和代谢信号到靶基因时起着关键作用。功能和结构研究阐明,协调激活因子通过一个和数个LXXLL基因序列(X为任意氨基酸,L为亮氨酸,也称NR盒)与ER受体上的激受诱导活化区域相互作用。采用酵母双杂交系统,确定了一种与ER-α相互作用的新蛋白质ERIAP(estrogen receptor-Interacting and activating protein,雌激素受体相互作用和活化蛋白),该蛋白质含有两个LXXLL基因序列。通过体内免疫沉淀和体外GST捕获方法分析,证明ERIAP以雌激素依赖性方式与ER-α相结合。ERIAP蛋白中的两个NR盒对其与ER-α相互作用是必要的。此外,ERIAP特异性提高雌激素诱导的ER-α转录活性,并增强雌激素响应基因pS2的表达。研究表明,ERIAP作为一新的ER-α转录活性协调激活因子,可能在乳腺癌的发生和发展中发挥重要的作用。展开更多
基金supported by the National Natural Science Foundation of China(Grant No.30128018)the National Institutes of Health,USA(Grant No.R21AA13122).
文摘Estrogen receptor (ER), one member of nuclear hormone receptor (NR) family, is an estrogen-dependent transcriptional factor that plays an important role in development, progression and treatment of breast cancer. Transcriptional co-factors (co-activators and co-repressors) are critical for ER to transduce hormone and metabolic signaling to target genes. A number of functional and structural studies have elucidated the precise mechanisms of co-activator interaction with the ligand-inducible activation domain in ER via one and several LXXLL motifs (where X is any amino acid) known as NR-Box. By the yeast two-hybrid system we have identified a novel ER-a interacting protein ERIAP (Estrogen Receptor Interacting and Activating Protein) which contains two consensus LXXLL motifs. ERIAP associated with ER-a in a ligand-dependent manner, as demonstrated by in vivo immunoprecipitation and in vitro GST capture assays. The two NR boxes were essential for ERIAP interaction with ER-a. Furthermore, ERIAP specifically enhanced ligand-mediated ER-a transcriptional activity in a dose-dependent fasion and increased the expression of estrogen-responsive gene pS2. Thus, our present findings indicate that ERIAP funcions as a new coactivator for ER-a transcriptional activity, which may play an important role in development and progression of breast cancer.
文摘雌激素受体(ER)属于核激素受体(NR)家族成员,是一种雌激素依赖性转录因子,在乳腺癌的发生、发展和治疗中起重要作用。协调转录因子(协调激活因子和协调抑制因子)在ER转导激素和代谢信号到靶基因时起着关键作用。功能和结构研究阐明,协调激活因子通过一个和数个LXXLL基因序列(X为任意氨基酸,L为亮氨酸,也称NR盒)与ER受体上的激受诱导活化区域相互作用。采用酵母双杂交系统,确定了一种与ER-α相互作用的新蛋白质ERIAP(estrogen receptor-Interacting and activating protein,雌激素受体相互作用和活化蛋白),该蛋白质含有两个LXXLL基因序列。通过体内免疫沉淀和体外GST捕获方法分析,证明ERIAP以雌激素依赖性方式与ER-α相结合。ERIAP蛋白中的两个NR盒对其与ER-α相互作用是必要的。此外,ERIAP特异性提高雌激素诱导的ER-α转录活性,并增强雌激素响应基因pS2的表达。研究表明,ERIAP作为一新的ER-α转录活性协调激活因子,可能在乳腺癌的发生和发展中发挥重要的作用。
