Identification of proteolytic signaling pathways regulating reprogramming during iPS cell generation

• Project/Area Number: 16K15811
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Dental engineering/Regenerative dentistry
• Research Institution: Tohoku University
• Principal Investigator: Inuzuka Hiroyuki 東北大学, 歯学研究科, 准教授 (20335863)
• Co-Investigator(Kenkyū-buntansha): 福本 敏 東北大学, 歯学研究科, 教授 (30264253) ; 福島 秀文 東北大学, 歯学研究科, 准教授 (70412624)
• Research Collaborator: SAWASAKI Tatsuya 愛媛大学, プロテオサイエンスセンター, 教授 ; SHIMIZU Kouhei 東北大学, 大学院歯学研究科, 助教
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: SKP2 / Ubiquitination / iPS cells / iPS / iPS細胞 / 蛋白質分解 / ユビキチン-プロテアソーム系 / iPS 細胞 / エピゲノム修飾

Outline of Final Research Achievements

Direct reprogramming of somatic cells to iPS cells involves global changes in epigenetic modification and gene expression. SKP2 E3 ligase is reported to play essential roles in epigenetic transcriptional regulation through degrading histone methyltransferases including MLL, PR-SET7, and CARM1. Here, to characterize the role of SKP2 signaling in human iPS generation, we conducted a screening of SKP2 interacting proteins and identified a RING-family protein as the E3 ligase of SKP2. Furthermore, we found that the protein levels of SKP2 and the RING E3 ligase are associated with the process of iPS generation. These data suggest that the identified E3 cascade may play important roles in epigenetic reprogramming of somatic to iPS cells.

Research Products

• [Int'l Joint Research] Beth Israel Deaconess Medical Center(米国)
• [Int'l Joint Research] Beth Israel Deaconess Medical Center(米国)
• [Journal Article] Skp2-dependent reactivation of AKT drives resistance to PI3K inhibitors (2018)
  • Author(s): Clement Emilie、Inuzuka Hiroyuki、Nihira Naoe T.、Wei Wenyi、Toker Alex
  • Journal Title: Science Signaling Volume: 11 Issue: 521 Pages: 3810-3810
  • DOI: 10.1126/scisignal.aao3810
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] NOTCH2 Hajdu-Cheney Mutations Escape SCFFBW7-Dependent Proteolysis to Promote Osteoporosis. (2017)
  • Author(s): Fukushima H, Shimizu K, Watahiki A, Hoshikawa S, Kosho T, Oba D, Sakano S, Arakaki M
  • Journal Title: Mol Cell Volume: Nov 16;68(4) Issue: 4 Pages: 645-658
  • DOI: 10.1016/j.molcel.2017.10.018
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prostate cancer-associated SPOP mutations confer resistance to BET inhibitors through stabilization of BRD4 (2017)
  • Author(s): Dai X, Gan W, Li X, Wang S, Zhang W, Huang L, Liu S, Zhong Q, Guo J, Zhang J, Chen T, Shimizu K, Beca F, Blattner M, Vasudevan D, Buckley DL, Qi J, Buser L, Liu P, Inuzuka H, Beck AH, Wang L, Wild PJ, Garraway LA, Rubin MA, Barbieri CE, Wong KK, Muthuswamy SK, Huang J, Chen Y, Bradner JE, Wei W
  • Journal Title: Nature Medicine Volume: 23 Issue: 9 Pages: 1063-1071
  • DOI: 10.1038/nm.4378
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] FBW7 loss promotes chromosomal instability and tumorigenesis via Cyclin E1/CDK2-mediated phosphorylation of CENP-A (2017)
  • Author(s): Takada M, Zhang W, Suzuki A, Kuroda T, Yu Z, Inuzuka H, Gao D, Wan L, Zhuang M, Hu L, Zhai B, Fry C, Bloom K, Li G, Karpen G, Wei W, Zhang Q
  • Journal Title: Cancer Research Volume: 77 Issue: 18 Pages: 4881-4893
  • DOI: 10.1158/0008-5472.can-17-1240
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Acetylation-dependent regulation of MDM2 E3 ligase activity dictates its oncogenic function. (2017)
  • Author(s): 2.Nihira NT, Ogura K, Shimizu K, North BJ, Zhang J, Gao D, Inuzuka H, Wei W.
  • Journal Title: Science Signaling Volume: 10 Issue: 466
  • DOI: 10.1126/scisignal.aai8026
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The APC/C E3 Ligase Complex Activator FZR1 Restricts BRAF Oncogenic Function (2017)
  • Author(s): Wan L, Chen M, Cao J, Dai X, Yin Q, Zhang J, Song SJ, Lu Y, Liu J, Inuzuka H, Katon JM, Berry K, Fung J, Ng C, Liu P, Song MS, Xue L, Bronson RT, Kirschner MW, Cui R, Pandolfi PP, Wei W
  • Journal Title: Cancer Discovery Volume: 7 Issue: 4 Pages: 424-441
  • DOI: 10.1158/2159-8290.cd-16-0647
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] G1 cyclins link proliferation, pluripotency and differentiation of embryonic stem cells (2017)
  • Author(s): Lijun Liu, Wojciech Michowski, Hiroyuki Inuzuka, Kouhei Shimizu, Naoe Taira Nihira, Joel M. Chick, Na Li, Yan Geng, Alice Y. Meng, Alban Ordureau, Aleksandra Kolodziejczyk, Keith L. Ligon, Roderick T. Bronson, Kornelia Polyak, J. Wade Harper, Steven P. Gygi, Wenyi Wei, Piotr Sicinski
  • Journal Title: Nature Cell Biology Volume: 19 Issue: 3 Pages: 177-188
  • DOI: 10.1038/ncb3474
  • Peer Reviewed / Int'l Joint Research
• [Presentation] タンパク質分解から考える骨及び脂質代謝制御 (2017)
  • Author(s): 犬塚 博之
  • Organizer: 第５５回日本小児歯科学会大会（シンポジウム）
  • Invited
• [Presentation] Multiple functions of SCF E3 ligase and its implications as a therapeutic target (2017)
  • Author(s): 犬塚 博之
  • Organizer: 第１５回 松山国際学術シンポジウム
  • Int'l Joint Research / Invited
• [Presentation] 抗アポトーシスタンパク質MCL1の安定性制御におけるアセチル化の役割 (2017)
  • Author(s): 清水 康平、犬塚 博之、福島 秀文、福本 敏
  • Organizer: 第５９回歯科基礎医学会学術大会
• [Presentation] BHD症候群関連タンパク質FNIP2のプロテアソーム依存的な量的調節機構の解析 (2016)
  • Author(s): 綿引 麻美、星川 聖良、犬塚 博之、江草 宏、福島 秀文
  • Organizer: 第39回 日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2016-11-30