Analysis of androgen-mediated p53 regulatory mechanism at transcriptional and protein levels

2017 Fiscal Year Final Research Report

• Project/Area Number: 15K15581
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Urology
• Research Institution: Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology (2016-2017); The University of Tokyo (2015)
• Principal Investigator: Takayama Ken-ichi 地方独立行政法人東京都健康長寿医療センター(東京都健康長寿医療センター研究所), 東京都健康長寿医療センター研究所, 研究員 (50508075)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: Prostate / p53 / Androgen / Nuclear export / G3BP2 / TRIM25 / USP10

Outline of Final Research Achievements

The androgen receptor (AR) has a central role in prostate cancer progression. Loss of the p53 tumor suppressor contributes to malignancy. We identified G3BP2 as a novel AR target involved in p53 signals by integrative sequence analysis. We then explored how G3BP2 modulates p53 activity and revealed that RanBP2, SUMO-E3 ligase, and TRIM25 are promising G3BP2-associating proteins in addition to known USP10. Mechanistically, translocation of p53 to cytoplasm was promoted by androgen-dependent sumoylation mediated by RanBP2. TRIM25 was indispensable for this complex formation and translocation of p53 to cytoplasm. Furthermore, G3BP2 expression is regulated at protein level through USP10-mediated inhibition of G3BP2 polyubiquitylation. Thus, G3BP2 has a repressive effect on p53 signaling through systematic interaction with RanBP2/TRIM25/USP10.

Free Research Field

内分泌　前立腺癌　アンドロゲン