Roles of sphingolipid metabolism on cell death by necroptosis

• Project/Area Number: 22592060
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Functional basic dentistry
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: YOKOYAMA Miki 東京医科歯科大学, 大学院・医歯学総合研究科, 准教授 (70191533)
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2012: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2011: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2010: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 口腔生化学 / 細胞死 / スフィンゴ脂質 / スフィンゴシンキナーゼ / S1P / ネクロプトーシス

Research Abstract

Sphingosine kinase (SPHK), which catalyzes the phosphorylation of sphingosine to generate sphingosine-1-phosphate, has two mammalian isotypes, SPHK1 and SPHK2. Both isozymes are promising anti-cancer therapeutic targets. In this study, we found that sphingosine and SG-12, a synthetic analogue of sphingosine that acts as a SPHK2 inhibitor, induce cell death via phosphorylation by SPHK1 and SPHK2, respectively. The present results revealed the novel anti-cancer potential of a sphingosine analogue in the pathological setting where SPHK2 is upregulated.

Research Products

• [Journal Article] Sphingosine kinase 2 inhibitor SG-12 induces apoptosis via phosphorylation by sphingosine kinase 2 (2013)
  • Author(s): Miki Hara-Yokoyama, Kazue Terasawa, Shizuko Ichinose, Akihiko Watanabe, Katarzyna A. Podyma-Inoue, Kazunari Akiyoshi, Yasuyuki Igarashi, Masaki Yanagishita
  • Journal Title: Bioorganic & Medicinal Chemistry Letters Volume: 23 Pages: 2220-2224
• [Journal Article] Tetrameric interaction of the ectoenzyme CD38 on the cell surface enables its catalytic and raft-association activities (2012)
  • Author(s): Miki Hara-Yokoyama, Mutsuko Kukimoto-Niino, Kazue Terasawa, Satoru Harumiya, Katarzyna A. Podyma-Inoue, Nobumasa Hino, Kensaku Sakamoto, Satsuki Itoh, Noritaka Hashii, Yoko Hiruta, Nana Kawasaki, Chiemi Mishima-Tsumagari, Yoko Kaitsu, Tomoko Matsumoto, Motoaki Wakiyama, Mikako Shirouzu, Takeshi Kasama, Hiroshi Takayanagi, Naoko Utsunomiya-Tate, Kiyoshi Takatsu, Toshiaki Katada, Yoshio Hirabayashi, Shigeyuki Yokoyama and Masaki Yanagishita
  • Journal Title: Structure Volume: 20 Pages: 1-11
• [Journal Article] Structural basis of interleukin-5 dimerrecognition by its α receptor (2012)
  • Author(s): Kusano S, Kukimoto-Niino M, Hino N, Ohsawa N, Ikutani M, Takaki S, Sakamoto K, Hara-Yokoyama M, Shirouzu M, Takatsu K, Yokoyama S
  • Journal Title: Protein Sci Volume: 21 Pages: 850-64
• [Journal Article] Syndecans reside insphingomyelin-enriched low-density fractions of the plasma membrane isolated from a parathyroid cell line (2012)
  • Author(s): Podyma-Inoue KA, Hara-Yokoyama M, Shinomura T, Kimura T, Yanagishita M
  • Journal Title: PLoS One Volume: 7(3)
• [Journal Article] Tetrameric interaction of the ectoenzyme CD38 on the cell surface enables its catalytic and raft-association activities (2012)
  • Author(s): Hara-Yokoyama M., Kukimoto-Niino M., Terasawa K., Harumiya S., Podyma-Inoue K. A., Hino N., Sakamoto K., Itoh S., Hashii N., Hiruta Y., Kawasaki N., Mishima-Tsumagari C., Kaitsu Y., Matsumoto T., Wakiyama M., Shirouzu M., Kasama T., Ta
  • Journal Title: Structure Volume: 20 Issue: 9 Pages: 1585-1595
  • DOI: 10.1016/j.str.2012.06.017
  • Peer Reviewed
• [Journal Article] Syndecans Reside in Sphingomyelin-Enriched Low-Density Fractions of the Plasma Membrane Isolated from a Parathyroid Cell Line (2012)
  • Author(s): Katarzyna A.Podyma-Inoue
  • Journal Title: PLoSOne Volume: 7
  • Peer Reviewed
• [Journal Article] Pocket epithelium in the pathological setting for HMGB1 release (2011)
  • Author(s): Ebe N, Hara-Yokoyama M, Iwasaki K, Iseki S, Okuhara S, Podyma-Inoue KA, Terasawa K, Watanabe A, Akizuki T, Watanabe H, Yanagishita M, Izumi Y
  • Journal Title: Journal of Dental Reserch Volume: 90 Pages: 235-40
• [Journal Article] Pocket Epithelium in the Pathological Setting for HMGB1 Release (2011)
  • Author(s): N.Ebe
  • Journal Title: Journal of Dental Research Volume: 90 Pages: 235-240
  • Peer Reviewed
• [Journal Article] Survival signals of hepatic stellate cells in liver regeneration are regulated by glycosylation changes in rat vitronectin, especially decreased sialylation (2010)
  • Author(s): Sano K, Miyamoto Y, Kawasaki N, Hashii N, Itoh S, Murase M, Date K, Yokoyama M, Sato C, Kitajima K, Ogawa H
  • Journal Title: J Biol Chem Volume: 285 Pages: 17301-17309
• [Presentation] CD38 の触媒活性と膜ドメイン局在化を両立させている細胞表面アセンブリの構造基盤 (2011)
  • Author(s): YOKOYAMA Miki, YOKOYAMA Shigeyuki, YANAGISHITA MASAKI
  • Organizer: 第40回日本免疫学会
  • Place of Presentation: 幕張
• [Presentation] 酪酸による酸化ストレス誘導時に放出されるHMGB1の役割 (2011)
  • Author(s): 江部典子、横山三紀、寺澤和恵、柳下正樹、和泉雄一
  • Organizer: 第135回日本歯科保存学会
  • Place of Presentation: 大阪
• [Presentation] Yanagishita, Characterization of Membrane Rafts Enriched in Cell Surface Heparan Sulfate Proteoglycans Isolated from a Rat Parathyroid Cell Line (2011)
  • Author(s): Katarzyna A. Podyma-Inoue, Miki Yokoyama, and Masaki
  • Organizer: 第84回日本生化学会
  • Place of Presentation: 京都
• [Presentation] GM2/GD2 合成酵素欠損マウスに おける血液ー精巣関門の異常 (2011)
  • Author(s): 横山三紀、市野瀬志津子、市野瀬省三、多田昇弘、寺澤和恵、吉垣純子、只野ー有冨桂子、古川鋼一、柳下正樹、岩渕和久
  • Organizer: 第84回日本生化学会
  • Place of Presentation: 京都
• [Presentation] リンパ球表面抗原CD38の四量体化を反映したN型糖鎖プロセシング (2011)
  • Author(s): 横山三紀、新野睦子、寺澤和恵、橋井則貴、蛭田葉子、川崎ナナ、脇山素明、白水美香子、横山茂之、柳下正樹
  • Organizer: 第30回日本糖質学会
  • Place of Presentation: 長岡
• [Presentation] Plasma membrane permeabilization-associated cell death induced by intracellular generation of sphingosine-1-phosphate (2011)
  • Author(s): Miki Yokoyama, Kazue Terasawa, ShizukoIchinose, Yoshiko Banno, YoshioHirabayashi, Yasuyuki Igarashi, Masaki Yanagishita
  • Organizer: The 30^<th> NAITO CONFERENCE ON Membrane Dynamics and Lipid Biology [II]
  • Place of Presentation: 札幌
• [Presentation] セラミド産生にともなうリソソーム関連膜構造物 (2011)
  • Author(s): 横山三紀、寺澤和恵、市野瀬志津子、柳下正樹
  • Organizer: 第53回日本脂質生化学会
  • Place of Presentation: 東京
• [Presentation] セラミド産生にともなうリソソーム関連膜構造物 (2011)
  • Author(s): 横山三紀
  • Organizer: 第53回日本脂質生化学会
  • Place of Presentation: ホテル東京ガーデンパレス
• [Presentation] リンパ球表面抗原CD38の四量体化を反映したN型糖鎖プロセシング (2011)
  • Author(s): 横山三紀
  • Organizer: 第30回日本糖質学会
  • Place of Presentation: 長岡リリックホール
• [Presentation] GM2/GD2合成酵素欠損マウスにおける血液-精巣関門の異常 (2011)
  • Author(s): 横山三紀
  • Organizer: 第84回日本生化学会
  • Place of Presentation: 京都国際会議場
• [Presentation] Plasma membrane permeabilization-associated cell death induced by intracellular generation of sphingosine-1-phosphate (2011)
  • Author(s): 横山三紀
  • Organizer: 第30回内糖コンファレンス
  • Place of Presentation: シャトレーゼガトーキングダム(札幌)
• [Presentation] CD38の触媒活性と膜ドメイン局在化を両立させている細胞表面でのアセンブリの構造基盤 (2011)
  • Author(s): 横山三紀
  • Organizer: 日本免疫学会総会
  • Place of Presentation: 幕張
• [Presentation] Increase in the plasma membrane permeability by intracellular gelleration of sphingosine-1-phosphate (2010)
  • Author(s): 横山三紀
  • Organizer: BMB2010(第83回日本生化学会大会・第33回日本分子生物学会年会合同大会)
  • Place of Presentation: 神戸
  • Year and Date: 2010-12-09
• [Presentation] スフィンゴシンキナーゼ2に依存した細胞膜透過性の亢進 (2010)
  • Author(s): 横山三紀
  • Organizer: 第5回スフィンゴテラピー会議
  • Place of Presentation: 米子
  • Year and Date: 2010-07-17
• [Presentation] スフィンゴシンキナーゼ2の酵素活性に依存したスフィンゴ脂質誘導体化合物による細胞死誘導 (2010)
  • Author(s): 横山三紀
  • Organizer: 第52回日本脂質生化学会
  • Place of Presentation: 伊香保
  • Year and Date: 2010-06-15
• [Presentation] Increase in the plasma membrane permeability by intracellular generation of sphingosine-1-phosphate (2010)
  • Author(s): Miki Yokoyama, Kazue Terasawa, ShizukoIchinose, Yoshiko Banno, YoshioHirabayashi, Yasuyuki Igarashi, Masaki Yanagishita
  • Organizer: 第83回日本生化学会大会
  • Place of Presentation: 神戸
• [Presentation] スフィンゴシンキナーゼ2の酵素活性に依存したスフィンゴ 脂質誘導体化合物による細胞死誘導 (2010)
  • Author(s): 横山三紀、寺澤和恵、五十嵐靖之、平林義雄、柳下正樹
  • Organizer: 第52回日本脂質生化学会
  • Place of Presentation: 伊香保