雄激素受体AR介导基因转录调控的辅调节因子筛选及生物学功能分析

项目名称： 雄激素受体AR介导基因转录调控的辅调节因子筛选及生物学功能分析

项目编号： No.30871390

项目类型： 面上项目

立项/批准年度： 2009

项目学科： 生物科学

项目作者： 赵越

作者单位： 中国医科大学

项目金额： 33万元

中文摘要： 雄激素受体(Androgen Receptor，AR)是核受体超家族成员之一。在配体存在下，AR与辅调节因子及其复合物结合调控下游靶基因的转录从而发挥其重要的生物学功能。AR及其辅调节因子在前列腺癌的生长增殖及去势抵抗等方面起关键作用。我们利用构建的AR-PEV果蝇模型筛选出数个AR辅调节因子，包括DNA损伤修复因子，RNA结合蛋白，组蛋白泛素化酶，蛋白激酶及功能未知的新因子等。本项目选择其中1个（hARAP1）进行深入研究。hARAP1主要含有FHA、BRCT蛋白结构域，是DNA 损伤修复过程中的重要因子。通过体外和体内实验证实hARAP1与AR相互作用，并上调AR介导的基因转录。通过大量的遗传学、分子细胞生物学、生物化学等实验研究，我们弄清了hARAP1参与上调转录的表观遗传学机制及其在前列腺癌中作用。实验结果表明hARAP1，组蛋白乙酰化酶GCN5，MYST1和AR共同招募到AR靶基因启动子区，GCN5的招募依赖于hARAP1的存在。同时我们还发现hARAP1上调抑癌基因p21的表达,并抑制前列腺癌细胞的增殖，表明ARAP1可能在前列腺癌发生发展中起重要作用。

中文关键词： 雄激素受体；转录调控；组蛋白修饰；p21;前列腺癌

英文摘要： Androgen receptor is a member of nuclear receptor super-family. In the presence of ligand, AR binds to co-regulator complex to modulate the transcription of target genes, and elaborates its important biological function. AR and its co-regulators play critical roles in prostate cancer growth, proliferation, castration-resistant and so on. By the established AR-PEV Drosophila experimental model, we screened and identified several AR co-regulators, including DNA damage repair factor, RNA binding protein, histone ubiquitinase, protein kinase and a novel factor with unknown function. One of them, named as hARAP1, was selected for the further study. hARAP1 mainly containing FHA and BRCT domains is a DNA damage repair factor. Our results demonstrated that hARAP1 associated with AR in vitro and in vivo, and up-regulated AR-induced transactivation. By the experiments of genetics, molecular cellular biology and biochemistry, we clarified the epigenetic mechanism of hARAP1 involved in the enhancement of transcription and its role in prostate cancer. We showed that hARAP1, histone acetyltransferase (GCN5), MYST1 and AR were recruited to the promoter of AR target genes; hARAP1 is required for the recruitment of GCN5. Meanwhile, we also found that hARAP1 enhanced the expression of p21, inhibited prostate cancer proliferation. Thus hARAP1 may play an important role in prostate cancer.

英文关键词： androgen receptor; modulation of transcrption; histone modification; p21; prostate cancer