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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）作为一种配体激活的转录因子，调节前列腺发育和肿瘤发生相关基因的表达。辅激活因子与AR结合并增强AR的转录活性，表明辅激活因子作为关键因子在AR转录激活中起重要作用。甘油醛-3-磷酸脱氢酶（GAPDH）在转移性前列腺癌细胞中高度表达，并受癌细胞生长的缺氧上调。我已经确定GAPDH作为AR辅激活剂。GAPDH可增强AR的反式激活，并在胞浆和细胞核中与AR形成蛋白复合物。此外，RanBP 10与RanBPM具有高度相似性，RanBPM是一种公认的AR共激活剂。RanBP 10增强配体依赖性AR反式激活并与AR形成复合物。RanBP 10在AR阳性前列腺癌细胞中高度表达，而RanBPM在非前列腺癌细胞中丰富。RanBP 10与RanBPM的共定位主要发生在细胞膜上。 ...更多信息从细胞质和细胞核中排出，并与自身或RanBPM形成蛋白质复合物，这表明RanBP 10作为同源寡聚体或与RanBPM的异源寡聚体增强AR反式激活。接下来，由于植物性饮食因子可能对人类癌发生具有化学预防作用，我将重点放在白藜芦醇的作用上，它抑制雄激素依赖性前列腺癌细胞中AR的功能。白藜芦醇抑制缺乏配体结合结构域的突变型AR（AR的组成性活性形式）和野生型AR的转录活性，表明白藜芦醇不通过与配体结合结构域结合来抑制AR反式激活。白藜芦醇处理的AR阳性前列腺癌细胞中AR蛋白的半衰期约为4小时，而对照细胞中约为13小时，表明白藜芦醇通过翻译后机制下调AR蛋白，并表明白藜芦醇对AR功能的抑制作用部分归因于翻译后AR水平的降低。少