Studies on G protein-coupled receptor controlling cell cycle and stemness

• Project/Area Number: 24390069
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Gunma University
• Principal Investigator: IZUMI TAKASHI 群馬大学, 医学(系)研究科(研究院), 教授 (70232361)
• Co-Investigator(Kenkyū-buntansha): 立井 一明 群馬大学, 医学(系)研究科(研究院), 准教授 (00192633) ; 大嶋 紀安 群馬大学, 医学(系)研究科(研究院), 助教 (30360514) ; 岸本 幸治 徳島大学, 生物資源産業学部, 講師 (50280699) ; 山本 正道 京都大学, 医学(系)研究科(研究院), 講師 (70423150)
• Project Period (FY): 2012-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥18,590,000 (Direct Cost: ¥14,300,000、Indirect Cost: ¥4,290,000); Fiscal Year 2015: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2014: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2013: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2012: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
• Keywords: 細胞医化学 / 細胞内シグナル伝達 / Gタンパク質共役受容体 / 酸化遊離脂肪酸 / 幹細胞性 / 細胞周期 / 幹細胞 / 受容体 / 脂質代謝 / G2A / 幹細胞性制御 / 細胞周期制御

Outline of Final Research Achievements

G2A is a G protein-coupled receptor that uses oxidized free fatty acids as ligands. The addition of oxidized free fatty acids such as 9-HODE to the cultured cells resulted in cell cycle arrest. G2A induction was also observed by stress stimulation such as glucose starvation and hypoxia. It became clear that G2A induction is deeply involved in changes in intracellular pH and glutathione concentration. When glioma cells expressing G2A were transplanted into immunodeficient mice, tumor-formation and metastasis to the organs was observed. Immunohistochemical analysis of metastatic lesion revealed that epithelial mesenchymal transition occurred.
Thus, G2A, a stress-inducible GPCR, stops the cell cycle in response to oxidized free fatty acids. On the other hand, G2A increases stemness in tumor cells resulting in epithelial mesenchymal transition and forms metastatic foci.

Research Products

• [Journal Article] Protein purification and cloning of diacylglycerol lipase from rat brain. (2016)
  • Author(s): Aso C, Araki M, Ohshima N, Tatei K, Hirano T, Obinata H, Kishi M, Kishimoto K, Konishi A, Goto F, Sugimoto H, Izumi T.
  • Journal Title: J. Biochem. Volume: 159 Issue: 6 Pages: 585-597
  • DOI: 10.1093/jb/mvw002
  • NAID: 40020869378
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Enzymatic characterization of recombinant rat DDHD2: a soluble diacylglycerol lipase. (2016)
  • Author(s): Araki M, Ohshima N, Aso C, Konishi A, Obinata H, Tatei K, Izumi T.
  • Journal Title: J. Biochem. Volume: 160 Issue: 5 Pages: 269-279
  • DOI: 10.1093/jb/mvw034
  • NAID: 40021012775
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Protein purification and cloning of diacylglycerol lipase from rat brain (2016)
  • Author(s): Chizu Aso, Mari Araki, Noriyasu Ohshima, Kazuaki Tatei, Tohko Hirano, Hideru Obinata, Mikiko Kishi, Koji Kishimoto, Fumio Goto, Hiroyuki Sugimoto, Takashi Izumi
  • Journal Title: J. Biochem. Volume: 印刷中
  • NAID: 40020869378
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] New members of the mammalian glycerophosphodiester phosphodiesterase family: GDE4 and GDE7 produce lysophosphatidic acid by lysophospholipase D activity. (2015)
  • Author(s): Ohshima N, Kudo T, Yamashita Y, Mariggio S, Araki M, Honda A, Nagano T, Isaji C, Kato N, Corda D, Izumi T, Yanaka N
  • Journal Title: J. Biol. Chem. Volume: 290 Issue: 7 Pages: 4260-4271
  • DOI: 10.1074/jbc.m114.614537
  • Peer Reviewed
• [Journal Article] Expression pattern of class I phosphoinositide 3-kinase and distribution of its product, phosphatidylinositol-3,4,5-trisphosphate, during Drosophila embryogenesis. (2014)
  • Author(s): Xi X, Tatei K, Kihara Y, Izumi T
  • Journal Title: Gene Expr. Patterns Volume: 15 Issue: 2 Pages: 85-89
  • DOI: 10.1016/j.gep.2014.06.001
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Spatial restriction of bone morphogenetic protein signaling in mouse gastrula through the mVam2-dependent endocytic pathway (2012)
  • Author(s): Aoyama, Wada et al.
  • Journal Title: Developmental Cell Volume: 22 Issue: 6 Pages: 1163-1175
  • DOI: 10.1016/j.devcel.2012.05.009
  • Peer Reviewed
• [Presentation] Purification and characterization of a soluble diacylglycerol lipase from rat brain (2015)
  • Author(s): Mari Araki, Chizu Aso, Noriyasu Ohshima, Kazuaki Tatei, Tohko Hirano, Hiroyuki Sugimoto, Mikiko Kishi, Koji Kishimoto, Hideru Obinata, Takashi Izumi
  • Organizer: 14th International Conference on Bioactive Lipids in Cancer, Inflammation and Related Diseases
  • Place of Presentation: Budapest, Hungary
  • Year and Date: 2015-07-12
  • Int'l Joint Research
• [Presentation] 新規リゾホスファチジン酸産生酵素、GDE4およびGDE7の酵素学的解析 (2015)
  • Author(s): 大嶋紀安、工藤 尊裕、山下洋祐、荒木麻理、伊佐治千明、本田絢子、長野友美、立井一明、加藤範久、矢中規之、和泉孝志
  • Organizer: 第５７回日本脂質生化学会
  • Place of Presentation: 一橋講堂、千代田区、東京
  • Year and Date: 2015-05-28
• [Presentation] Identification and functional analyses of a novel diacylglycerol lipase from rat brain (2015)
  • Author(s): Araki M, Aso C, Ohshima N, Tatei K, Hirano T, Sugimoto H, Kishi M, Kishimoto K, Izumi T
  • Organizer: The 6th International Conference on PLA2 and Lipid Mediators
  • Place of Presentation: 東京都、新宿区、京王プラザホテル
  • Year and Date: 2015-02-09 – 2015-02-12
• [Presentation] GDE4 and GDE7 Produce Lysophosphatidic Acid by Lysophospholipase D Activity (2015)
  • Author(s): Isaji C, Kudo T, Ohshima N, Yamashita Y, Araki M, Honda A, Nagano T, Kato N, Konishi A, Kishimoto K, Tatei K, Yanaka N, Izumi T
  • Organizer: The 6th International Conference on PLA2 and Lipid Mediators
  • Place of Presentation: 東京都、新宿区、京王プラザホテル
  • Year and Date: 2015-02-09 – 2015-02-12
• [Presentation] Quantitative Analysis of Oxygen in Living Cells and Tissues Using Iridium(III) Complexes with Cationic Substituent (2014)
  • Author(s): Yoshihara T, Hosaka M, Kishimoto K, Akiyama H, Tobita S
  • Organizer: GUMI & AMDE 2014
  • Place of Presentation: 群馬県、桐生市、桐生市民文化会館
  • Year and Date: 2014-12-05
• [Presentation] ラット脳ジアシルグリセロールリパーゼの精製と機能解析 (2014)
  • Author(s): 大嶋紀安、荒木麻理、麻生千寿、立井一明、岸本幸治、和泉孝志
  • Organizer: 生体情報研究シンポジウム
  • Place of Presentation: 秋田県、秋田市、秋田キャッスルホテル
  • Year and Date: 2014-08-07
• [Presentation] Gタンパク質共役型受容体、G2Aが制御するがん幹細胞性と上皮間葉転換 (2014)
  • Author(s): 岸本幸治、原口崇、清水健志、山口藍子、井出宗則、吉原利忠、大嶋紀安、飯田靖彦、飛田成史、対島義人、小山徹也、和泉孝志
  • Organizer: 第23回日本がん転移学会学術集会
  • Place of Presentation: 石川県、金沢市、金沢市文化ホール
  • Year and Date: 2014-07-10 – 2014-07-11
  • Invited
• [Presentation] 9-HODE-activated G2A induces epithelial-to-mesenchymal transition of human astrocytoma cells prior to generation of stem cell-like properties. (2013)
  • Author(s): Koji Kishimoto, Takashi Haraguchi, Kenji Shimizu, Aiko Yamaguchi, Toshitada Yoshihara, Noriyasu Ohshima, Kazuaki Tatei, Seiji Tobita, Yasuhiko Iida, Yoshito Tsushima, Takashi Izumi
  • Organizer: 北米神経科学会2013
  • Place of Presentation: サンディエゴ、カリフォルニア、アメリカ
• [Presentation] Gタンパク質共役型受容体、G2Aはアストロサイトーマ細胞株のがん幹細胞性を制御する (2013)
  • Author(s): 岸本幸治、原口崇、清水健志、山口藍子、吉原利忠、大島紀安、立井一明、飛田成史、飯田靖彦、対島義人、和泉孝志
  • Organizer: 第８６回日本生化学会大会
  • Place of Presentation: 神奈川県、横浜、パシフィコ横浜
• [Presentation] 新規脳ジアシルグリセロールリパーゼの同定 (2013)
  • Author(s): 荒木麻理, 麻生知寿, 大嶋紀安, 立井一明, 平野瞳子, 杉本博之, 岸美紀子, 岸本幸治, 和泉孝志
  • Organizer: 第５５回日本脂質生化学会
  • Place of Presentation: 宮城県、松島
• [Presentation] Subcellular distribution and binding specificity of phospholipid-binding proteins. (2013)
  • Author(s): Xi Xin, Kazuaki Tatei, Hideaki Ehara, Yumiko Kihara, Takashi Izumi
  • Organizer: 第５５回日本脂質生化学会
  • Place of Presentation: 宮城県、松島
• [Presentation] ヒトアストロサイトーマU251細胞の幹細胞性と上皮間葉転換制御に関わるG2Aの役割 (2012)
  • Author(s): 原川崇
  • Organizer: 第85回日本生化学会大会
  • Place of Presentation: 福岡国際会議場(福岡県)
  • Year and Date: 2012-12-15
• [Presentation] Oxidized free fatty acids-activated GPCR, G2A regulates sternness and malignant behavior of an astrocytoma cell line. (2012)
  • Author(s): Koji Kishimoto
  • Organizer: 北米神経科学会Society of Neuroscience 2012
  • Place of Presentation: 米国、ニューオリンズ市
  • Year and Date: 2012-10-16
• [Presentation] G2A Regulates Stemness and malignant behavior of Astrocytoma Cells. (2012)
  • Author(s): Koji Kishimoto
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: ロイトン札幌(札幌市)
  • Year and Date: 2012-09-20
• [Presentation] がん幹細胞性制御におけるG2Aの役割 (2012)
  • Author(s): 岸本幸治
  • Organizer: 日本生化学会関東支部例会
  • Place of Presentation: 刀城会館(前橋市)
  • Year and Date: 2012-06-23
• [Presentation] Gタンパク質共役型受容体、G2Aを介したがん幹細胞性制御 (2012)
  • Author(s): 岸本幸治
  • Organizer: 第54回日本脂質生化学会
  • Place of Presentation: 九州大学(福岡市)
  • Year and Date: 2012-06-07