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

雄激素受体（AR）是一种配体激活的转录因子，调节参与前列腺发育和肿瘤发生的基因表达。共激活因子与AR结合，增强AR的转录活性，表明共激活因子作为关键因子在AR的转录活化中发挥重要作用。甘油醛-3-磷酸脱氢酶（GAPDH）在转移性前列腺癌细胞中高表达，并在癌细胞生长的缺氧条件下上调表达。我已经确定GAPDH作为AR辅激活剂。GAPDH增强AR的反式活化，并在胞浆和细胞核中与AR形成蛋白复合物。此外，RanBP10与RanBPM具有很高的相似性，RanBPM是一种成熟的AR共激活剂。RanBP10增强配体依赖性AR的转激活，与AR形成复合物。RanBP10在AR阳性前列腺癌细胞中高表达，而RanBPM在非前列腺癌细胞中表达丰富。RanBP10主要与RanBPM共定位，更多地通过细胞质和细胞核与自身或RanBPM形成蛋白复合物，提示RanBP10以RanBPM的同质寡聚物或异质寡聚物的形式增强AR的转激活。其次，由于植物性饮食因子可能对人类癌变具有化学预防作用，笔者重点研究了白藜藜醇在雄激素依赖性前列腺癌细胞中抑制AR功能的作用。白藜芦醇抑制了缺乏配体结合域的AR突变体（AR的组成活性形式）和野生型AR的转录活性，表明白藜芦醇不会通过与配体结合域的结合来抑制AR的转激活。在白藜芦醇处理的AR阳性前列腺癌细胞中，AR蛋白的半衰期约为4小时，而在对照细胞中约为13小时，这表明白藜芦醇通过翻译后机制下调AR蛋白，并提示白藜芦醇对AR功能的抑制作用部分归因于翻译后AR水平的降低。少

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