Modulation of lipid homeostasis in maintenance and directed differentiation of mesenchymal stem cells

• Project/Area Number: 16H05529
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• 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) ; 齋藤 正寛 東北大学, 歯学研究科, 教授 (40215562) ; 竹田 浩之 愛媛大学, プロテオサイエンスセンター, 准教授 (40609393) ; 福島 秀文 東北大学, 歯学研究科, 准教授 (70412624)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2018: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2017: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2016: ¥8,840,000 (Direct Cost: ¥6,800,000、Indirect Cost: ¥2,040,000)
• Keywords: タンパク質分解 / 脂質代謝 / Lipin1 / beta-TRCP / 間葉系幹細胞 / 歯髄幹細胞 / SCF/beta-TRCP / 蛋白質分解 / ユビキチン-プロテアソーム系

Outline of Final Research Achievements

Manipulating lipid biosynthesis in stem cells could be a potential approach for highly efficient directed differentiation of mesenchymal stem cells. In this study, we identified the molecular mechanisms of the proteasome-dependent degradation of Lipin1 that plays critical roles in lipid homeostasis. Our finding will provide insights into the development of novel strategies for the directed differentiation of mesenchymal stem cells through Lipin1 protein stability control.

Academic Significance and Societal Importance of the Research Achievements

再生医療研究において間葉系幹細胞の応用が進められているが、幹細胞代謝研究領域での脂質代謝調節に焦点を当てた研究は少ない。薬理学的および遺伝学的アプローチにより脂質合成制御が幹細胞で可能となれば、効率的な細胞分化誘導のほか移植後細胞の脂肪細胞分化転換抑制にも応用可能となることから、本研究で得られた知見は高効率かつ安定的な幹細胞分化誘導法開発の基礎となると期待される。

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] Physiological functions of FBW7 in cancer and metabolism (2018)
  • Author(s): Shimizu Kouhei、Nihira Naoe Taira、Inuzuka Hiroyuki、Wei Wenyi
  • Journal Title: Cellular Signalling Volume: 46 Pages: 15-22
  • DOI: 10.1016/j.cellsig.2018.02.009
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] SCFβ-TRCP E3 ubiquitin ligase targets the tumor suppressor ZNRF3 for ubiquitination and degradation (2018)
  • Author(s): Ci Yanpeng、Li Xiaoning、Chen Maorong、Zhong Jiateng、North Brian J.、Inuzuka Hiroyuki、He Xi、Li Yu、Guo Jianping、Dai Xiangpeng
  • Journal Title: Protein & Cell Volume: 9 Issue: 10 Pages: 879-889
  • DOI: 10.1007/s13238-018-0510-2
  • Peer Reviewed / Int'l Joint Research
• [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] SCFFBW7-mediated degradation of Brg1 suppresses gastric cancer metastasis (2018)
  • Author(s): Huang Li-Yu、Zhao Junjie、Chen Hao、Wan Lixin、Inuzuka Hiroyuki、Guo Jianping、Fu Xuhong、Zhai Yangyang、Lu Zhaoning、Wang Xuefei、Han Ze-Guang、Sun Yihong、Wei Wenyi
  • Journal Title: Nature Communications Volume: 9 Issue: 1 Pages: 3569-3569
  • DOI: 10.1038/s41467-018-06038-y
  • Peer Reviewed / Open Access / 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 Pages: 4881-4893
  • 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] 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
• [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] The SCFβ-TRCP E3 ubiquitin ligase complex targets Lipin1 for ubiquitination and degradation to promote hepatic lipogenesis. (2017)
  • Author(s): Shimizu K, Fukushima H, Ogura K, Lien EC, Nihira NT, Zhang J, North BJ, Guo A, Nagashima K, Nakagawa T, Hoshikawa S, Watahiki A, Okabe K, Yamada A, Toker A, Asara JM, Fukumoto S, Nakayama KI, Nakayama K, Inuzuka H, Wei W.
  • Journal Title: Sci Signal. doi: 10.1126/scisignal.aah4117. Volume: 10 Issue: 460 Pages: 1-15
  • DOI: 10.1126/scisignal.aah4117
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Nutrient-induced FNIP degradation by SCFβ-TRCP regulates FLCN couplex localization and promotes renal cancer progression (2016)
  • Author(s): Nagashima, K., Fukushima, H., Shimizu, K., Hidaka, M., Hasumi, H., Ikebe, T., Fukumoto, S., Okabe, K., Inuzuka, H.
  • Journal Title: Oncotarget Volume: 8 Issue: 6 Pages: 9947-9960
  • DOI: 10.18632/oncotarget.14221
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Regulation of cell survival through post-translational modifications of MCL-1 in tumorigenesis (2019)
  • Author(s): Hiroyuki Inuzuka, Kouhei Shimizu, Mitsuki Chiba, Satoshi Fukumoto, Wenyi Wei
  • Organizer: The Kick-off Symposium of Advanced Graduate Program for Future Medicine and Health Care
  • Invited
• [Presentation] ユビキチン-プロテアソーム経路の破綻によるMCL1安定化機構とその制御方法の検討 (2018)
  • Author(s): 清水 康平、千葉 満生、犬塚 博之、福本 敏
  • Organizer: 第60回歯科基礎医学会学術大会
• [Presentation] プロテアソーム阻害剤を用いた効率的骨芽細胞分化誘導法の検討 (2018)
  • Author(s): 星川 聖良、千葉 満生、綿引 麻美、清水 康平、犬塚 博之、福本 敏
  • Organizer: 第60回歯科基礎医学会学術大会
• [Presentation] Notch2 変異を介した骨粗鬆症病態の分子機構解明 (2018)
  • Author(s): 犬塚 博之
  • Organizer: 第41回日本分子生物学会年会ワークショップ
  • Invited
• [Presentation] Lipin 2タンパク質分解を介したマクロファージ活性化調節機構の解析 (2018)
  • Author(s): 綿引麻美、清水康平、瓜生英尚、星川聖良、福本敏、江草宏、犬塚博之
  • Organizer: 第41回日本分子生物学会年会
• [Presentation] Analysis of proteasome-dependent lipogenic pathway in hepatocytes (2017)
  • Author(s): Seira Hoshikawa, Asami Watahiki, Hidefumi Fukushima, Satoshi Fukumoto, Hiroyuki Inuzuka
  • Organizer: Japan-NIH Joint Symposium
  • Place of Presentation: Sendai
  • Year and Date: 2017-02-15
  • 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] 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] 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] 脂質代謝におけるSCF ユビキチンリガーゼの機能と役割 (2016)
  • Author(s): 犬塚 博之
  • Organizer: 第70回 東北大学歯学会
  • Place of Presentation: 仙台
  • Year and Date: 2016-12-02
  • Invited
• [Presentation] ユビキチン－プロテアソーム系を介した肝細胞脂質合成経路の解析 (2016)
  • Author(s): 星川 聖良、綿引 麻美、福島 秀文、福本 敏、犬塚 博之
  • 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
• [Presentation] 脂質代謝における SCF beta-TRCPユビキチンリガーゼ複合体の役割 (2016)
  • Author(s): 犬塚 博之, 福島 秀文, 清水 康平, Wenyi Wei, 福本 敏
  • Organizer: 第58回 歯科基礎医学会学術大会
  • Place of Presentation: 札幌
  • Year and Date: 2016-08-24
  • Invited