Role of PU.1 suppressive target gene, metallothionein, as a forecasting biomarker for anticancer agents

• Project/Area Number: 26460685
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Laboratory medicine
• Research Institution: Tohoku Medical and Pharmaceutical University (2016-2017); Kitasato University (2014-2015)
• Principal Investigator: TAKAHASHI Shinichiro 東北医科薬科大学, 医学部, 教授 (40375069)
• Project Period (FY): 2014-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: メタロチオネイン / 抗がん剤 / 効果予測マーカー

Outline of Final Research Achievements

We previously identified a multifunctional factor, metallothionein (MT), as a myeloid master transcription factor PU.1 suppressive target gene. We previously revealed that MT strongly suppresses all-trans retinoid acid induced acute promyelocytic leukemia (NB4) cells differentiation. In this study, we revealed that MT not only inhibits myeloid cell differentiation, but also bears activity for drug resistance, especially for cytarabine (Ara-C). We revealed that the MT over-expressed NB4 cells bears 1.5 to 2.0 times higher ED50 doses of Ara-C compared to their controls.

Research Products

• [Int'l Joint Research] Centre Hospitalier Universitaire/Amiens-Picardie, 80054 Amiens Cedex 1(フランス)
• [Journal Article] Metallothionein-1 as a biomarker of altered redox metabolism in hepatocellular carcinoma cells exposed to sorafenib (2016)
  • Author(s): Houessinon A, François C, Sauzay C, Louandre C, Mongelard G, Godin C, Bodeau S, Takahashi S, Saidak Z, Gutierrez L, Régimbeau JM, Barget N, Barbare JC, Ganne N, Chauffert B, Coriat R, Galmiche A
  • Journal Title: Mol Cancer Volume: 15 Issue: 1 Pages: 38-38
  • DOI: 10.1186/s12943-016-0526-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] PU.1標的遺伝子の同定による新たな骨髄球系細胞分化機構の解明 (2016)
  • Author(s): 高橋伸一郎
  • Journal Title: 生化学 Volume: 88 Pages: 233-236
• [Journal Article] Internal tandem duplication and tyrosine kinase domain mutations in FLT3 alter the response to daunorubicin in Ba/F3 cells (2016)
  • Author(s): Takahashi S and Shirahama K
  • Journal Title: Biomedical Reports Volume: Jan 4(1) Pages: 83-86
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Positive and negative regulators of metallothionein gene (2015)
  • Author(s): Takahashi S
  • Journal Title: Molecular Medicine Reports Volume: in press Issue: 1 Pages: 795-799
  • DOI: 10.3892/mmr.2015.3459
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] A PU.1 suppressive target gene, metallothionein 1G, inhibits retinoic acid-induced NB4 cell differentiation (2014)
  • Author(s): Hirako N, Nakano H, Takahashi S
  • Journal Title: PLOS ONE Volume: 9 Issue: 7 Pages: e103282-e103282
  • DOI: 10.1371/journal.pone.0103282
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Allo-antigen stimulated CD8+ T cells Suppress NF-κB and Ets-1 DNA Binding Activity, and Inhibit Phosphorylated NF-κB p65 Nuclear Localization in CD4+ T cells (2014)
  • Author(s): Nagashima R, Kawakami F, Takahashi S, Obata F, Kubo M
  • Journal Title: Viral Immunology Volume: 27 Issue: 6 Pages: 305-315
  • DOI: 10.1089/vim.2013.0113
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] The differentiation effect of low dose cytosine arabinoside is disturbed in PU.1-knockdown K562 cells (2014)
  • Author(s): Nakano H, Yanagita A, Takahashi S
  • Journal Title: Biomedical Reports Volume: 2 Issue: 4 Pages: 564-568
  • DOI: 10.3892/br.2014.265
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] 急性骨髄性白血病と遺伝子異常 (2017)
  • Author(s): 高橋伸一郎
  • Organizer: 第7回日本検査血液学会東北支部学術集会
  • Invited
• [Presentation] 急性骨髄性白血病と遺伝子異常～遺伝子異常から分かる病態と未来 (2017)
  • Author(s): 高橋伸一郎
  • Organizer: 第49回みやぎ医学検査学会
  • Invited
• [Presentation] PU.1標的遺伝子メタロチオネインの単球系分化における機能の解明 (2017)
  • Author(s): 高渕優太朗、泉義彦、張替秀郎、高橋伸一郎
  • Organizer: 第7回日本検査血液学会東北支部学術集会
• [Presentation] 稀な染色体異常であるt(10;18)を伴う骨髄異形成症候群の一例 (2017)
  • Author(s): 大場祐輔、皆川忠徳、渡部卓、櫻田明美、齊藤梨絵、浅野裕子、藤田智咲、泉義彦、藤原実名美、高橋伸一郎
  • Organizer: 第18回日本検査血液学会学術集会
• [Presentation] Signal regulatory protein (SIRP) a1発現抑制K562細胞は低血清培養化で異常増殖を示す (2016)
  • Author(s): 髙橋 伸一郎
  • Organizer: 第64回日本輸血・細胞治療学会
  • Place of Presentation: 国立国際会議場（京都府・京都市）
  • Year and Date: 2016-04-29
• [Presentation] Downregulation of SIRPa1 results in the aberrant cell growth in low serum culture (2015)
  • Author(s): Takahashi S, Waki H, Nakano H
  • Organizer: 日本血液学会
  • Place of Presentation: 石川県立音楽堂ほか（金沢市、石川県）
  • Year and Date: 2015-10-16
• [Presentation] PU.1標的遺伝子MTの好中球分化における役割 (2015)
  • Author(s): 高橋伸一郎
  • Organizer: メタルバイオサイエンス研究会2015
  • Place of Presentation: 名古屋国際センター（名古屋、愛知県）
  • Year and Date: 2015-08-27
  • Invited
• [Presentation] メタロチオネイン1G発現の顆粒球分化効率予測因子としての可能性 (2015)
  • Author(s): 高橋伸一郎
  • Organizer: 日本輸血・細胞治療学会
  • Place of Presentation: 京王プラザホテル（新宿、東京都）
  • Year and Date: 2015-05-28
• [Presentation] Detection of Anti-Thrombopoietin antibodies in patients with immune thrombocytopenia (2014)
  • Author(s): Satoh T, Miyazaki T, Osawa E, Modegi N, Kita A, Kurihara S, Kawasaki Y, Shimada N, Nagane K, Higashihara M, Takahashi S
  • Organizer: American Society of Hematology Meeting
  • Place of Presentation: San Diego Convention Center, San Diego, USA
  • Year and Date: 2014-12-08
• [Presentation] 急性前骨髄性白血病(NB4)細胞におけるメタロチオネイン1G過剰発現の細胞分化・ストレス反応への影響 (2014)
  • Author(s): 平子奈緒美、中野博子、高橋伸一郎
  • Organizer: 日本分子生物学会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2014-11-26
• [Presentation] Analysis of anti-thrombopoietin antibody in patients with immune thrombocytopenia (2014)
  • Author(s): Satoh T, Miyazaki K, Shimada N, Nagane K, Kita A, Kurihara S, Kawasaki Y, Kodaira Y, Osawa E, Modegi N, Higashihara M, Takahashi S
  • Organizer: 日本血液学会
  • Place of Presentation: 大阪国際会議場（大阪府大阪市）
  • Year and Date: 2014-11-02
• [Presentation] メタロチオネイン1-Gの過剰発現は全トランス型レチノイン酸による急性前骨髄球性白血病細胞分化を阻害する (2014)
  • Author(s): 高橋伸一郎
  • Organizer: 日本検査血液学会
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2014-07-20
• [Presentation] Detection of anti-thrombopoietin autoantibody among immune thrombocytopenic patients (2014)
  • Author(s): Miyazaki T, Satoh T, Osawa E, Modegi N, Kita A, Kurihara S, Kawasaki Y, Shimada N, Nagane K, Higashihara M, Takahashi S
  • Organizer: 19th Congress of European Hematology Association Meeting
  • Place of Presentation: Milano Congressi, Milan, Italy
  • Year and Date: 2014-06-13
• [Presentation] 免疫性血小板減少症におけるトロンボポエチンに対する自己抗体の解析 (2014)
  • Author(s): 佐藤隆司、宮崎浩二、大沢絵莉子、茂出木菜穂美、 喜多晃子、栗原紗恵子、川崎友里、小平祐衣、東原正明、高橋伸一郎
  • Organizer: 日本血栓止血学会学術集会
  • Place of Presentation: 大阪国際交流センター（大阪府大阪市）
  • Year and Date: 2014-05-31
• [Remarks] 研究室案内 東北医科薬科大学医学部臨床検査医学
  • URL: http://www.tohoku-mpu.ac.jp/medicine/about/kensa/
• [Remarks] 東北医科薬科大学医学部 研究室案内 臨床検査医学
  • URL: http://www.tohoku-mpu.ac.jp/medicine/about/kensa/
• [Remarks] 北里大学医療衛生学部医療検査学科血液学研究室ホームページ
  • URL: http://www.kitasato-u.ac.jp/ahs/ml/ketsueki/
• [Remarks] 大学プレスセンター 北里大学が顆粒球系細胞分化を制御する遺伝子を新たに同定
  • URL: http://www.u-presscenter.jp/modules/bulletin/index.php?page=article&storyid=7318