Study on the bio-active molecule, DIF, found in the cellular slime mold Dictyostelium discoideum

• Project/Area Number: 24590110
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Biological pharmacy
• Research Institution: Juntendo University (2015); Gunma University (2012-2014)
• Principal Investigator: Kubohara Yuzuru 順天堂大学, スポーツ健康科学研究科, 教授 (00221937)
• Co-Investigator(Kenkyū-buntansha): KOJIMA Itaru 群馬大学, 生体調節研究所, 教授 (60143492) ; OSHIMA Yoshiteru 東北大学, 大学院薬学研究科, 教授 (00111302)
• Project Period (FY): 2012-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 細胞性粘菌 / DIF / がん / 糖尿病 / ミトコンドリア / 走化性運動 / トリパノソーマ / 免疫

Outline of Final Research Achievements

DIF-1, a low-molecular weight compound found in the cellular slime mold Dictyostelium discoideum, and its derivatives possess multiple biological activities, such as anti-proliferative and glucose-uptake-promoting activities in vitro in mammalian cells. We have investigated the pharmacological functions of DIFs and indicated that DIFs may be good lead compounds for the development of novel anti-tumor, anti-obesity/anti-diabetes, and anti-Trypanosoma drugs. In addition, we have found that DIFs may function, at least in part, by disturbing mitochondrial activity in mammalian cells.

Research Products

• [Journal Article] Differentiation-inducing factor 2 modulates chemotaxis via the histidine kinase DhkC-dependent pathway in Dictyostelium discoideum. (2016)
  • Author(s): Kuwayama H, & Kubohara Y.
  • Journal Title: FEBS Lett. Volume: 590 Issue: 6 Pages: 760-768
  • DOI: 10.1002/1873-3468.12111
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Derivatives of Dictyostelium differentiation-inducing factors inhibit lysophosphatidic acid–stimulated migration of murine osteosarcoma LM8 cells. (2015)
  • Author(s): Kubohara Y, Komachi M, Homma Y, Kikuchi H, & Oshima Y.
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 463 Issue: 4 Pages: 800-805
  • DOI: 10.1016/j.bbrc.2015.06.016
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Development of novel DIF-1 derivatives that selectively suppress innate immune responses. (2015)
  • Author(s): Nguyen VH, Kikuchi H, Kubohara Y, Takahashi K, Katou Y, & Oshima Y.
  • Journal Title: Bioorg. Med. Chem. Volume: 23 Issue: 15 Pages: 4311-4315
  • DOI: 10.1016/j.bmc.2015.06.027
  • Peer Reviewed
• [Journal Article] A Derivative of Differentiation-Inducing Factor-3 Inhibits PAK1 Activity and Breast Cancer Cell Proliferation. (2015)
  • Author(s): Oladimeji P, Kubohara Y, Kikuchi H, Oshima Y, Rusch C, Skerl R, & Diakonova M.
  • Journal Title: Int. J. Cancer Clinic. Res. Volume: 2 Pages: 3-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Properties of a non-bioactive fluorescent derivative of differentiation-inducing factor-3, an anti-tumor agent found in Dictyostelium discoideum. (2014)
  • Author(s): Kubohara Y, Kikuchi H, Matsuo Y, Oshima Y, & Homma Y.
  • Journal Title: Biology Open Volume: 3 Issue: 4 Pages: 289-296
  • DOI: 10.1242/bio.20146585
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Chlorinated Dibenzofurans Isolated from the Cellular Slime Mold, Polysphondylium filamentosum, and Their Biological Activities (2013)
  • Author(s): Kikuchi, H.; Kubohara, Y.; Nguyen, V. H.; Katou, Y.; Oshima, Y. Novel
  • Journal Title: Bioorg. Med. Chem Volume: (In press) Issue: 15 Pages: 4628-4633
  • DOI: 10.1016/j.bmc.2013.05.022
  • Peer Reviewed
• [Journal Article] The Dictyostelium prestalk inducer DIF-1 directs phosphorylation of a bZIP transcription factor. (2013)
  • Author(s): Yamada Y, Kubohara Y, Kikuchi H, Oshima Y, Wang HY, Ross S, & Williams JG.
  • Journal Title: Intenational Journal of Developmental Biology Volume: 57 Issue: 5 Pages: 375-381
  • DOI: 10.1387/ijdb.130046jw
  • Peer Reviewed
• [Journal Article] Mitochondria are the target organelle of differentiation-inducing factor-3, an anti-tumor agent isolated from Dictyostelium discoideum. (2013)
  • Author(s): Kubohara Y, Kikuchi H, Matsuo Y, Oshima Y, & Homma Y.
  • Journal Title: PLoS One Volume: 8 Issue: 8 Pages: e72118-e72118
  • DOI: 10.1371/journal.pone.0072118
  • Peer Reviewed
• [Journal Article] Derivatives of Dictyostelium discoideum differentiation-inducing factor-3 suppress the activities of Trypanosoma cruzi in vitro and in vivo (2013)
  • Author(s): Nakajima-Shimada J, Hatabu T, Hosoi Y, Onizuka Y, Kikuchi H, Oshima Y, & Kubohara Y
  • Journal Title: Biochemical Pharmacology Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Manganese promotes phorbol ester–induced interleukin-2 production via AP-1 activation in Jurkat T-cells (2012)
  • Author(s): Tanaka S, Masuda Y, Honma C, Hosaka K, Takahashi K, & Kubohara Y
  • Journal Title: Toxicology Letters Volume: 211 Issue: 3 Pages: 312-318
  • DOI: 10.1016/j.toxlet.2012.04.015
  • Peer Reviewed
• [Journal Article] Isolation, Synthesis and Biological Activity of Biphenyl and m-Terphenyl-Type Compounds from Dictyostelium Cellular Slime Molds (2012)
  • Author(s): Kikuchi, H.; Matsuo, Y.; Katou, Y.; Kubohara, Y.; Oshima, Y
  • Journal Title: Tetrahedron Volume: 68 Issue: 43 Pages: 8884-8889
  • DOI: 10.1016/j.tet.2012.08.041
  • Peer Reviewed
• [Presentation] Jurkat T細胞においてマイトジェン刺激で活性化される転写調節因子のマンガンによる影響 (2015)
  • Author(s): 中島徹、田中進、田中佑季、秋山珠璃、久保原禅、保坂公平
  • Organizer: 日本生化学会第88回大会
  • Place of Presentation: 京都国際会議場（京都府京都市）
  • Year and Date: 2015-12-03
• [Presentation] DIF-2による粘菌走化性運動の制御メカニズム (2015)
  • Author(s): 桑山秀一、久保原禅
  • Organizer: 日本細胞性粘菌学会第5回例会
  • Place of Presentation: 弘前大学（青森県弘前市）
  • Year and Date: 2015-10-10
• [Presentation] １型糖尿病モデルラットの血糖値に対するDIF-1（経口投与）の効果 (2015)
  • Author(s): 河原田律子、中村彰男、高橋克典、菊地晴久、大島吉輝、久保原禅
  • Organizer: 日本細胞性粘菌学会第5回例会
  • Place of Presentation: 弘前大学（青森県弘前市）
  • Year and Date: 2015-10-10
• [Presentation] ヒトがん細胞が高発現するマーカーとオリゴ糖添加による影響 (2015)
  • Author(s): 牧岡優佳、山本菜々子、久保原禅、細見修
  • Organizer: 第29回日本キチン・キトサン学会大会
  • Place of Presentation: 東海大学熊本キャンパス（熊本県熊本市）
  • Year and Date: 2015-08-20
• [Presentation] Glutathione S-transferase 4 (GST4) is a putative binding protein for DIFs that regulate the size of fruiting bodies in D. discoideum (2014)
  • Author(s): 久保原禅、菊地晴久、大島吉輝、桑山秀一
  • Organizer: 日本細胞性粘菌学会第４回例会
  • Place of Presentation: 東北大学（仙台）
  • Year and Date: 2014-10-11
• [Presentation] 細胞性粘菌由来化合物DIF-1誘導体の自然免疫抑制作用とその構造活性相関 (2014)
  • Author(s): Van Hai Nguyen、菊地晴久、久保原禅、大島吉輝
  • Organizer: 日本細胞性粘菌学会第４回例会
  • Place of Presentation: 東北大学（仙台）
  • Year and Date: 2014-10-11
• [Presentation] 生物活性の無いDIF-3蛍光体の特性
  • Author(s): 久保原禅、菊地晴久、松尾祐介、大島吉輝、本間好
  • Organizer: 日本細胞性粘菌学会
  • Place of Presentation: 京都大学
• [Presentation] 南米シャーガス病の病原虫トリパノソーマに対するDIFの効果
  • Author(s): 嶋田淳子、細井友夏里、畑生俊光、菊地晴久、大島吉輝、久保原禅
  • Organizer: 日本細胞性粘菌学会
  • Place of Presentation: 京都大学
• [Presentation] HeLa細胞におけるDIF蛍光体の局在と機能
  • Author(s): 久保原禅、菊地晴久、松尾祐介、大島吉輝、本間好
  • Organizer: 日本細胞性粘菌学会第２回例会
  • Place of Presentation: 東京大学
  • Invited
• [Presentation] 細胞性粘菌由来の薬理活性物質によるインターロイキン-2(IL-2)発現制御
  • Author(s): 高橋克典，村上正巳，菊池晴久，大島吉輝，久保原禅
  • Organizer: 第59回日本臨床検査医学学術集会
  • Place of Presentation: 京都国際会館
  • Invited
• [Book] 細胞性粘菌（研究の新展開）～モデル生物、創薬資源、バイオ～ (2012)
  • Author(s): 阿部知顕、前田靖男（編著）、久保原禅 他（著）
  • Total Pages: 552
  • Publisher: アイピーシー社
• [Remarks] 順天堂大学 研究者情報データベース
  • URL: https://www.juntendo.ac.jp/graduate/kenkyudb/search/researcher.php?MID=5490
• [Remarks] 群馬大学生体調節研究所遺伝子情報分野
  • URL: http://molgen.imcr.gunma-u.ac.jp
• [Remarks] 群馬大学生体調節研究所遺伝子情報分野
  • URL: http://www.imcr.gunma-u.ac.jp/lab/molgen/
• [Patent(Industrial Property Rights)] アミド誘導体 (2014)
  • Inventor(s): 菊地晴久、大島吉輝、服部俊夫、久保原禅、他
  • Industrial Property Rights Holder: 東北大学、群馬大学、扶桑薬品工業株式会社
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2014-038919
  • Filing Date: 2014-02-21
• [Patent(Industrial Property Rights)] ジクチオピロン誘導体又はジヒドロジクチオピロン誘導体を有効成分とするオステオポンチン産生阻害剤 (2013)
  • Inventor(s): 菊地晴久、大島吉輝、服部俊夫、久保原禅、他
  • Industrial Property Rights Holder: 群馬大学、東北大学、扶桑薬品工業株式会社
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2013-046197
  • Filing Date: 2013-03-08