| Budget Amount *help |
¥3,690,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2007: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2006: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Research Abstract |
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
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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
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