新規生理活性脂質の生体機能

• Project/Area Number: 13GS0012
• Research Category: Grant-in-Aid for Creative Scientific Research
• Allocation Type: Single-year Grants
• Research Institution: Gunma University
• Principal Investigator: 和泉 孝志 群馬大学, 大学院医学系研究科, 教授 (70232361)
• Co-Investigator(Kenkyū-buntansha): 杉本 博之 獨協医科大学, 医学部, 教授 (00235897) ; 立井 一明 群馬大学, 大学院医学系研究科, 講師 (00192633) ; 新井 洋由 東京大学, 大学院薬学系研究科, 教授 (40167987) ; 青木 淳賢 東京大学, 大学院薬学系研究科, 助教授 (20250219)
• Project Period (FY): 2001 – 2005
• Project Status: Completed (Fiscal Year 2005)
• Budget Amount: ¥339,950,000 (Direct Cost: ¥282,500,000、Indirect Cost: ¥57,450,000); Fiscal Year 2005: ¥78,650,000 (Direct Cost: ¥60,500,000、Indirect Cost: ¥18,150,000); Fiscal Year 2004: ¥79,300,000 (Direct Cost: ¥61,000,000、Indirect Cost: ¥18,300,000); Fiscal Year 2003: ¥91,000,000 (Direct Cost: ¥70,000,000、Indirect Cost: ¥21,000,000); Fiscal Year 2002: ¥91,000,000 (Direct Cost: ¥91,000,000)
• Keywords: 生理活性脂質 / Gタンパク質共役型受容体 / ロイコトリエン / リゾホスファチジン酸 / 2-アラキドノイルグリセロール / 5-リポキシゲナーゼ / リン脂質生合成 / 酸化遊離脂肪酸 / オーファン受容体 / ホスホリパーゼ / 血小板活性化因子

Research Abstract

1.オーファン受容体G2Aの新規リガンドの発見
DNA損傷やストレス刺激で誘導されるG2Aと呼ばれるオーファン受容体についてリガンドスクリーニングを行ったところ、9-HODEや11-HETEなどのリノール酸やアラキドン酸などの不飽和脂肪酸の酸化物がリガンドとして働くことを発見した。シグナルの解析を進めると同時にその生理的意義について解明した。特に、皮膚由来初代培養細胞における紫外線によるG2A誘導とその炎症反応における意義を解明した。
2.生理活性脂質産生に関する研究
脳におけるリゾホスファチジン酸および2-アラキドノイルグリセロールの産生機序を解明する目的で、ラット脳から産生酵素の部分精製を行い、新規の酵素によるこれら生理活性脂質の産生機序並びに酵素学的性質を明らかにした。また、ロイコトリエン産生に関与する5-リポキシゲナーゼのストレス誘導性の核外輸送経路を明らかにした。
3.リゾリン脂質ならびにその受容体の生体機能に関する研究
リゾホスファチジン酸受容体(LPA3)の着床ならびにその後の胎児発生における働きを解明した。また、EBウィルスによる、LPA産生酵素(オートタキシン)の誘導がホジキンリンパ腫の増殖に関与することを明らかにした。
4.リン脂質生合成に関する研究
膜リン脂質の主要成分であるボスファチジルコリン合成の律速酵素であるCTαの転写調節機構を解明し、そのプロモータ領域に強力な転写抑制因子Netが結合すると細胞増殖抑制作用を発揮することを、培養細胞系を用いて明らかにした。

Research Products

• [Journal Article] Sp1 is a co-activator with Ets-1, and Net is an important repressor of the transcription of CTP : photocholine cytidylyltransferase alpha (2005)
  • Author(s): Sugimoto, H., et al.
  • Journal Title: J Biol Chem. 280・49 Pages: 40857-40866
• [Journal Article] Identification of 9-hydroxyoctadecadienoic acid and other oxidized free fatty acids ligands of the G protein-coupled receptor G2A (2005)
  • Author(s): Obinata, H., et al.
  • Journal Title: J Biol Chem. 280・49 Pages: 40676-40683
• [Journal Article] Stress-induced nuclear export of 5-lipoxygenase (2005)
  • Author(s): Hanaka, H., et al.
  • Journal Title: Biochem Biophys Res Commun 338・1 Pages: 111-116
• [Journal Article] LPA3-mediated lysophosphatidic acid signalling in embryo implantation and spacing (2005)
  • Author(s): Ye, X., et al.
  • Journal Title: Nature 435・7038 Pages: 104-108
• [Journal Article] Biochemical and molecular characterization of a novel choline-specific glycerophosphodiester phosphodiesterase belonging to the nucleotide pyrophosphatase/phosphodiesterase family (2005)
  • Author(s): Sakagami, H., et al.
  • Journal Title: J Biol Chem 280・24 Pages: 23084-23093
• [Journal Article] Induction of autotaxin by the Epstein-Barr virus promotes the growth and survival of Hodgkin lymphoma cells (2005)
  • Author(s): Baumforth, K. R., et al.
  • Journal Title: Blood 106・6 Pages: 2138-2146
• [Journal Article] Lethal malaria in cytosolic phospholipase A2- and phospholipase A2IIA-deficient mice. (2004)
  • Author(s): Ishikawa, S., et al.
  • Journal Title: Am J Trop Med Hyg 70・6 Pages: 645-650
• [Journal Article] Over-expression of lysophophatidic acid receptor-2 in human invasive ductal carcinoma. (2004)
  • Author(s): Kitayama, J., et al.
  • Journal Title: Breast Cancer Res. 6・6
• [Journal Article] Dual mode regulation of migration by lysophosphatidic acid in human gastric cancer cells. (2004)
  • Author(s): Shida, D., et al.
  • Journal Title: Exp Cell Res. 301・2 Pages: 168-178
• [Journal Article] Type II platelet-activating factor-acetylhydrolase is essential for epithelial morphogenesis in Caenorhabditis elegans. (2004)
  • Author(s): Inoue, T., et al.
  • Journal Title: Proc Natl Acad Sci U S A 101・36 Pages: 13233-13238
• [Journal Article] Prostatic acid phosphatase degrades lysophosphatidic acid in seminal plasma. (2004)
  • Author(s): Tanaka, M., et al.
  • Journal Title: FEBS Lett. 571・1-3 Pages: 197-204
• [Journal Article] Lysophosphatidic acid and autotaxin stimulate cell motility of neoplastic and non-neoplastic cells through LPA1. (2004)
  • Author(s): Hama, K., et al.
  • Journal Title: J Biol Chem. 279・17 Pages: 17634-17639
• [Patent(Industrial Property Rights)] Gタンパク質共役型受容体G2Aの作動薬、及びG2A活性調節薬のスクリーニング方法 (2005)
  • Inventor(s): 和泉 孝志, 大日方 英
  • Industrial Property Rights Holder: 群馬大学
  • Industrial Property Number: 2005-182051
  • Filing Date: 2005-06-22
• [Publications] Obinata, H., et al.: "Glucocorticoids up-regulate leukotriene B4 receptor-1 expression during neutrophilic differentiation in HL-60 Cells."Biochem Biophys Res Comm. 309・1. 114-119 (2003)
• [Publications] Sugimoto, H., et al.: "Identification of Ets-1 as an important transcriptional activator, of CTP : phosphocholine cytidylyltransferase alpha in COS-7 cells and co-activation with transcriptional enhancer factor-4."J Biol Chem. 278・22. 19716-19722 (2003)
• [Publications] Suzuki, M., et al.: "Actin assembly is a crucial factor for superoxide anion generation from adherent human eosinophils."J Allergy Clin Immunol. 112・1. 126-133 (2003)
• [Publications] Hasegawa, Y., et al.: "Identification of a phosphothionate analogue of lysophosphatidic acid (LP3) as a selective agonist of the LPAS receptor."J Biol Chem. 278・14. 11962-11969 (2003)
• [Publications] Koizumi, H., et al.: "Targeted disruption of intracellular type I platelet activating factor-acetylhydrolase catalytic subunits causes severe impairment in spermatogenesis."J Biol Chem. 278・14. 12489-12494 (2003)
• [Publications] Hiramatsu, T.et al.: "Biochemical and molecular characterization of two phosphatidic acid-selective phospholipase A1s, mPA-PLA 1 alpha and mPA-PLA 1 beta."J Biol Chem. 278・49. 49438-49447 (2003)
• [Publications] Oshima, N., et al.: "Receptor-dependent metabolism of platelet-activating factor in murine macrophages"J Biol Chem. 277・12. 9722-9727 (2002)
• [Publications] Ogasawara, H., et al.: "Characterization of mouse cysteinyl leukotriene receptors, mCysLT1 and mCysLT2 : Differential pharamacological properties and tissue distribution"J Biol Chem. 277・12. 18763-18768 (2002)
• [Publications] Takizawa, T., et al.: "Inhibition of protein kinase A and C demonstrates dual modes of response in hunma eosinophils stimulated by platelet-activating factor"J. Allergy Clin. Immunol. 110・2. 241-248 (2002)
• [Publications] Sonoda, H., et al.: "A novel phosphatidic acid-selective phospholipase A1 that produces lysophosphatidic acid"J Biol Chem. 277・37. 34254-34263 (2002)
• [Publications] Aoki J., et al.: "Serum lysophosphatidic acid is produced through diverse phospholipase pathways"J Biol Chem. 277・50. 48737-48744 (2002)
• [Publications] Umezu-Goto, M. et al.: "Autotaxin has lysophospholipase activity leading to leading to tumor cell growth and motility by lysophosphatidic acid production"J Cell Biol. 158・2. 227-233 (2002)
• [Publications] Hosono, H., et al.: "Phosphatidylserine-specific phospholipase Al stimulates histamine release from rat peritoneal mast cells through production of 2-acyl-1-lysophosphatidylserine"J.Biol.Chem.. 276・32. 29664-29670 (2001)
• [Publications] Yokomizo, T., et al.: "Co-expression of two LTB4 receptors in human mononuclear cells"Life Science. 68・19. 2207-2212 (2001)
• [Publications] Yokomizo, T., et al.: "Hydroxyeicosanoids bind to and activate the low affinity leukotriene B4 receptor, BLT2"J.Biol.Chem.. 276・15. 12454-12459 (2001)
• [Publications] Mizuno, S., et al.: "Role of PAF in acute liver injury after extended hepatectomy : Overexpression of PAF receptor mRNA on Kupffer cells"Digestive Dis. Sci.. 46・6. 1299-1304 (2001)
• [Publications] Hayashi, K., et al.: "Phenotypic modulation of vascular smooth muscle cells induced by unsaturated lysophosphatidic acids"Circ.Res.. 89・3. 251-258 (2001)
• [Publications] Hanaka, H., et al.: "Nuclear-localization-signal-dependent and nuclear-export-signal-dependent mechanisms determine the localization of 5-lipoxygenase"Biochem.J.. 361・3. 505-514 (2002)