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人类ADA3与雌激素受体(ER)结合,并作为ER介导的反式激活的共激活因子发挥作用。

Human ADA3 binds to estrogen receptor (ER) and functions as a coactivator for ER-mediated transactivation.

作者信息

Meng Gaoyuan, Zhao Yongtong, Nag Alo, Zeng Musheng, Dimri Goberdhan, Gao Qingshen, Wazer David E, Kumar Rakesh, Band Hamid, Band Vimla

机构信息

Department of Radiation Oncology, New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.

出版信息

J Biol Chem. 2004 Dec 24;279(52):54230-40. doi: 10.1074/jbc.M404482200. Epub 2004 Oct 20.

Abstract

We have recently identified the hADA3 protein, the human homologue of yeast transcriptional coactivator yADA3, as a novel HPV16 E6 target. Using ectopic expression approaches, we further demonstrated that hADA3 directly binds to the 9-cis retinoic acid receptors alpha and beta, and functions as a coactivator for retinoid receptor-mediated transcriptional activation. Here, we examined the role of endogenous hADA3 as a coactivator for estrogen receptor (ER), an important member of the nuclear hormone receptor superfamily. We show that ADA3 directly interacts with ER alpha and ER beta. Using the chromatin immunoprecipitation assay, we also show that hADA3 is a component of the activator complexes bound to the native ER response element within the promoter of the estrogen-responsive gene pS2. Furthermore, using an ER response element-luciferase reporter, we show that overexpression of ADA3 enhances the ER alpha- and ER beta-mediated sequence-specific transactivation. Reverse transcription-PCR analysis showed an ADA3-mediated increase in estrogen-induced expression of the endogenous pS2 gene. More importantly, using RNA interference against hADA3, we demonstrate that inhibition of endogenous hADA3 inhibited ER-mediated transactivation and the estrogen-induced increase in the expression of pS2, cathepsin D, and progesterone receptor, three widely known ER-responsive genes. The HPV E6 protein, by targeting hADA3 for degradation, inhibited the ER alpha-mediated transactivation and the protein expression of ER target genes. Thus, our results demonstrate that ADA3 directly binds to human estrogen receptor and enhances the transcription of ER-responsive genes, suggesting a broader role of mammalian hADA3 as a coactivator of nuclear hormone receptors and the potential role of these pathways in HPV oncogenesis.

摘要

我们最近鉴定出hADA3蛋白,即酵母转录共激活因子yADA3的人类同源物,是一种新的人乳头瘤病毒16型(HPV16)E6靶点。通过异位表达方法,我们进一步证明hADA3直接与9-顺式视黄酸受体α和β结合,并作为类视黄醇受体介导的转录激活的共激活因子子发挥因子发挥作用。在此,我们研究了内源性hADA3作为雌激素受体(ER)共激活因子的作用,ER是核激素受体超家族的一个重要成员。我们发现ADA3直接与ERα和ERβ相互作用。使用染色质免疫沉淀分析,我们还发现hADA3是与雌激素反应基因pS2启动子内天然ER反应元件结合的激活复合物的一个组成部分。此外,使用ER反应元件-荧光素酶报告基因,我们发现ADA3的过表达增强了ERα和ERβ介导的序列特异性反式激活。逆转录-聚合酶链反应分析显示ADA3介导内源性pS2基因雌激素诱导表达增加。更重要的是,使用针对hADA3的RNA干扰,我们证明内源性hADA3的抑制抑制了ER介导的反式激活以及雌激素诱导的pS2、组织蛋白酶D和孕激素受体这三个广为人知的ER反应基因表达增加。HPV E6蛋白通过靶向降解hADA3,抑制了ERα介导的反式激活以及ER靶基因的蛋白表达。因此,我们的结果表明ADA3直接与人雌激素受体结合并增强ER反应基因的转录,提示哺乳动物hADA3作为核激素受体共激活因子具有更广泛的作用以及这些途径在HPV肿瘤发生中的潜在作用。

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