Study on Mechanisms by which hypoxia-associated proteins regulate androgen receptor signaling

缺氧相关蛋白调节雄激素受体信号传导机制研究

基本信息

批准号：
18580127
负责人：
YAMAJI Ryoichi
金额：
$ 2.36万
依托单位：
Osaka Prefecture University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

项目摘要

Androgen receptor (AR) acts as a ligand-activated transcription factor that regulates the expression of genes involved in prostate development and tumorigenesis. Coactivators bind to AR and enhance the transcriptional activity of AR, indicating that coactivators play an important role in AR transactivation as a key factor. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is highly expressed in metastatic prostate cancer cells and up-regulated by hypoxia in which cancer cells grow. I have identified that GAPDH acts as an AR coactivator. GAPDH enhanced AR transactivation and formed a protein complex with AR in both cytosol and nucleus. Furthermore, RanBP10 shares high similarity with RanBPM that is a well-established AR coactivator. RanBP10 enhanced the ligand-dependent AR transactivation and formed a complex with AR. RanBP10 was highly expressed in AR-positive prostate cancer cells, whereas RanBPM was abundant in non-prostate cancer cells. RanBP10 was mostly co-localized with RanBPM thr … More oughout the cytoplasm and nucleus and formed a protein complex with itself or RanBPM, suggesting that RanBP10 enhances AR transactivation as a homo-oligomer or a hetero-oligomer with RanBPM Next, because plant-based dietary factors may have chemopreventive effects on human carcinogenesis, I have focused on the role of resveratrol, which inhibits the function of the AR in androgen-dependent prostate cancer cells. Resveratrol repressed the transcriptional activities of a mutant AR lacking the ligand-binding domain, a constitutive active form of AR, and wild-type AR, indicating that resveratorol does not inhibit AR transactivation through binding to the ligand-binding domain. The half life of AR protein was approximately 4 h in resveratrol-treated AR-positive prostate cancer cells, compared to approximately 13 h in control cells, indicating that resveratrol down-regulates AR protein through a post-translational mechanism and suggest that inhibitory effect of resveratrol on AR function is partly attributable to a decrease in the post-translational AR level. Less

雄激素受体（AR）充当配体激活的转录因子，可调节参与前列腺发育和肿瘤发生的基因的表达。共激活因子与AR结合并增强AR的转录活性，表明共激活因子在AR反式激活中起重要作用是关键因素。 3-磷酸甘油醛脱氢酶（GAPDH）在转移性前列腺癌细胞中高度表达，并由癌细胞生长的缺氧上调。我已经确定GAPDH充当AR共激活因子。 GAPDH增强了AR反式激活，并在细胞质和核中形成了与AR的蛋白质复合物。此外，RANBP10与ranbpm具有很高的相似性，RANBPM是一个完善的AR共激活因子。 RANBP10增强了配体依赖性AR的反式激活，并与AR形成复合物。 RANBP10在AR阳性前列腺癌细胞中高度表达，而RANBPM主要与Ranbpm共定位……更多的是细胞质和细胞核，并与自身或RANBPM形成蛋白质复合物，表明RANBP10与AR AR与同型同型抗体相关，因为ranbp10 ranbp1基于植物的饮食因素可能对人类致癌作用产生化学预防作用，我专注于白藜芦醇的作用，白藜芦醇抑制了AR在雄激素依赖性前列腺癌细胞中的功能。白藜芦醇反映了缺乏配体结合结构域的突变体AR的转录活性，AR的组成型活性形式和野生型AR，表明依克氏硫醇不会通过与配体结合域结合而抑制AR反式激活。在白藜芦醇处理的AR阳性前列腺癌细胞中，AR蛋白的半寿命约为4小时，而对照细胞中约有13小时，白藜芦醇通过后翻译机制下调AR蛋白，并表明白藜芦醇对AR功能对AR功能的抑制作用是可将其抑制作用的一部分，这是一定程度的降低的。较少的