Post-translational modification of transcription factors regulates on-off switch of cell proliferation

• Project/Area Number: 15K09464
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Tohoku University
• Principal Investigator: Minegishi Naoko 東北大学, 東北メディカル・メガバンク機構, 教授 (40271895)
• Co-Investigator(Kenkyū-buntansha): 勝岡 史城 東北大学, 東北メディカル・メガバンク機構, 准教授 (30447255)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 血液腫瘍学 / 転写因子 / GATA因子 / 細胞周期制御 / 翻訳後調節 / 翻訳語調節 / 白血病

Outline of Final Research Achievements

GATA2 is an essential transcription factor for hematopoiesis. We analyzed the cell-cycle dependent post-translational regulation of this factor. The expression level of GATA2 and its binding to target sequences, were low in early G1 phase, then increased in G1-S transition phase. In the late S phase, GATA2 expression increased but GATA2 binding to its target sequences decreased. In M-phase, Cyclin B1-Cyclin-dependent kinase (CDK)1 phosphorylated T176 residue of GATA2, and induced the interaction with F-box/WD repeat -containing protein 7 (Fbw7) and the ubiquitin-mediated degradation of GATA2. GATA2 was also phosphorylated by Cyclin A/E-CDK2 and interacted with S-phase kinase-associated protein 2 (Skp2), which is known as a ubiquitin-conjugating enzyme of phosphorylated cyclin-dependent kinase inhibitor 1B (p27) in G1-S phase. Thus, GATA2 is under the regulation of cell-cycle specific serine/threonine phosphorylation and ubiquitin-mediated degradation.

Academic Significance and Societal Importance of the Research Achievements

GATA2は多くの造血器腫瘍に発現するほか、GATA２欠損症では前白血病から白血病の発症や、血液・免疫系の細胞の減少による免疫不全状態が報告されている。一方、ユビキチン・プロテアソーム系は造血器腫瘍治療の重要な標的経路であり、本課題の成果を発端として、今後、この経路とGATA２による細胞増殖のより詳細な関係が明らかにされ、これら疾患の病態解明や治療法の開発につながることが期待される。

Research Products

• [Journal Article] Maternity Log study: a longitudinal lifelog monitoring and multiomics analysis for the early prediction of complicated pregnancy (2019)
  • Author(s): Sugawara J, Ochi D, Yamashita R, Yamauchi T, Saigusa D, Wagata M, Obara T, Ishikuro M, Tsunemoto Y, 18名略, Hiyama S, Nagasaki M
  • Journal Title: BMJ Open Volume: 9(2) Issue: 2 Pages: e025939-e025939
  • DOI: 10.1136/bmjopen-2018-025939
  • Peer Reviewed / Open Access
• [Journal Article] Development of a Highly Sensitive Device for Counting the Number of Disease-Specific Exosomes in Human Sera. (2018)
  • Author(s): Kabe Y, Suematsu M, Sakamoto S, Hirai M, Koike I, Hishiki T, Matsuda A, Hasegawa Y, Tsujita K, Ono M, Minegishi N, Hozawa A, Murakami Y, Kubo M, Itonaga M, Handa H.
  • Journal Title: Clin Chem Volume: 64 Issue: 10 Pages: 1463-1473
  • DOI: 10.1373/clinchem.2018.291963
  • Peer Reviewed / Open Access
• [Journal Article] Functional characterization of 40 CYP2B6 allelic variants by assessing efavirenz 8-hydroxylation (2018)
  • Author(s): Watanabe Takashi、Saito Takahiro、Rico Evelyn Marie Gutierrez、Hishinuma Eiji、Kumondai Masaki、Maekawa Masamitsu、Oda Akifumi、Saigusa Daisuke、Saito Sakae、Yasuda Jun、Nagasaki Masao、Minegishi Naoko、Yamamoto Masayuki、Yamaguchi Hiroaki、Mano Nariyasu、Hirasawa Noriyasu、Hiratsuka Masahiro
  • Journal Title: Biochemical Pharmacology Volume: 156 Pages: 420-430
  • DOI: 10.1016/j.bcp.2018.09.010
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Omics research project on prospective cohort studies from the Tohoku Medical Megabank Project. (2018)
  • Author(s): Koshiba, S., （途中略）, Yamamoto, M.（合計２１名、本研究者は１番目）
  • Journal Title: Genes Cells Volume: 23 Issue: 6 Pages: 406-417
  • DOI: 10.1111/gtc.12588
  • Peer Reviewed / Open Access
• [Journal Article] Genome analyses for the Tohoku Medical Megabank Project towards establishment of personalized healthcare (2018)
  • Author(s): Yasuda Jun、Kinoshita Kengo、et al.,
  • Journal Title: The Journal of Biochemistry Volume: 165 Issue: 2 Pages: 139-158
  • DOI: 10.1093/jb/mvy096
  • NAID: 40021809939
  • Peer Reviewed / Open Access
• [Journal Article] Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes (2018)
  • Author(s): Malik R, Chauhan G, Traylor M, Minegishi N, AFGen Consortium,BioBank Japan Cooperative Hospital Group; MEGASTROKE Consortium
  • Journal Title: Nat Genet Volume: 50 Issue: 4 Pages: 524-537
  • DOI: 10.1038/s41588-018-0058-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Construction of full-length Japanese reference panel of class I HLA genes with single-molecule, real-time sequencing (2018)
  • Author(s): Mimori T, Fumiki K, Sakae S、Naoki N, 、Akira O, Minegishi N, Kinoshita K, Nagasaki M, Yamamoto M
  • Journal Title: Pharmacogenomics Volume: 63 Issue: 2 Pages: 213-230
  • DOI: 10.1038/s41397-017-0010-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Evaluation of reported pathogenic variants and their frequencies in a Japanese population based on a whole-genome reference panel of 2,049 individuals (2018)
  • Author(s): Y Yamaguchi-Kabata, J Yasuda, O Tanabe, Y Suzuki, H Kawame, N Fuse, M Nagasaki, Y Kawai, K Kojima, F Katsuoka, S Saito, I Danjoh, I Motoike, R Yamashita, S Koshiba, D Saigusa, G Tamiya, S Kure, N Yaegashi, Y Kawaguchi, F Nagami, S Kuriyama, J Sugawara, N Minegishi, A Hozawa, T Takai-Igarashi, K Kinoshita, M Yamamoto.
  • Journal Title: Journal of Human Genetics. Volume: 63 Issue: 2 Pages: 213-230
  • DOI: 10.1038/s10038-017-0347-1
  • Peer Reviewed / Open Access
• [Journal Article] Genome-wide association study identifies 112 new loci for body mass index in the Japanese population (2017)
  • Author(s): Akiyama M, Okada Y, Kanai M, Takahashi A, Momozawa Y, Ikeda M, Iwata N, Ikegawa S, Hirata M, Matsuda K, Iwasaki M, Yamaji T, Sawada N, Hachiya T, Tanno K, Shimizu A, Hozawa A, Minegishi N, Tsugane S, Yamamoto M, Kubo M and Kamatani Y
  • Journal Title: Nat Genet Volume: 49 Issue: 10 Pages: 1458-1462
  • DOI: 10.1038/ng.3951
  • Peer Reviewed / Open Access
• [Journal Article] Security controls in an integrated Biobank to protect privacy in data sharing: rationale and study design (2017)
  • Author(s): Takai-Igarashi T, Kinoshita K, Nagasaki M, Ogishima S, Nakamura N, Nagase S, Nagaie S, Saito T, Nagami F, Minegishi N, Suzuki Y, Suzuki K, Hashizume H, Kuriyama S, Hozawa A, Yaegashi N, Kure S, Tamiya G, Kawaguchi Y, Tanaka H, Yamamoto M
  • Journal Title: BMC Med Inform Decis Mak Volume: 17 Issue: 1 Pages: 100-100
  • DOI: 10.1186/s12911-017-0494-5
  • Peer Reviewed / Open Access
• [Journal Article] 503 Genome-wide association study identifies novel susceptibility loci for tanning ability in Japanese population (2017)
  • Author(s): Shido K., Kojima K, Hozawa A, Ogishima S, Minegishi N, Kawai Y, Tamiya G, Tanno K, Yamasaki K, and Aiba S
  • Journal Title: J Invest Dermatol Volume: 137
  • Peer Reviewed
• [Journal Article] Contribution of a Population-Based Biobank to Improving the Health Status of the Japanese Population (2017)
  • Author(s): Minegishi N, Yamashita R, Nobukuni T, Nishijima I, Kudo H, Terakawa T, Ishida N, Hozawa A, Tomita H, Nagasaki M, Yamamoto M, Tohoku Medicak Megabank Project Study Group
  • Journal Title: Biopreservation and biobanking Volume: 15
  • Peer Reviewed
• [Journal Article] Renal Anemia Model Mouse Established by Transgenic Rescue with an Erythropoietin Gene Lacking Kidney-Specific Regulatory Elements (2017)
  • Author(s): Hirano I, Suzuki N, Yamazaki S, Sekine H, Minegishi N, Shimizu R, Yamamoto M.
  • Journal Title: Mol Cell Biol Volume: 37 Issue: 4
  • DOI: 10.1128/mcb.00451-16
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Genetic predisposition to ischemic stroke: A polygenic risk score (2017)
  • Author(s): Hachiya T, Kamatani Y, Takahashi A, Hata J, Furukawa R, Shiwa Y, Yamaji T, Hara M, Tanno K, Ohmomo H, Ono K, Takashima N, Matsuda K, Wakai K, Minegishi N, et.al
  • Journal Title: Stroke Volume: 48 Pages: 253-258
  • Peer Reviewed
• [Journal Article] The structural origin of metabolic quantitative diversity. (2016)
  • Author(s): Koshiba S, Motoike I, Kojima K, Hasegawa T, Shirota M, Saito T, Saigusa D, Danjoh I, Katsuoka F, Ogishima S, ... Yamamoto M.
  • Journal Title: Sci Rep Volume: 6 Issue: 1 Pages: 31463-31463
  • DOI: 10.1038/srep31463
  • Peer Reviewed / Open Access
• [Journal Article] The Tohoku Medical Megabank Project: Design and Mission (2016)
  • Author(s): Kuriyama S, Yaegashi N, et al. (Tamiya G; 11th in 58 authors)
  • Journal Title: Journal of Epidemiology Volume: 26 Issue: 9 Pages: 493-511
  • DOI: 10.2188/jea.JE20150268
  • NAID: 130005409018
  • ISSN: 0917-5040, 1349-9092
  • Peer Reviewed / Open Access
• [Journal Article] Unique cistrome defined as CsMBE is strictly required for Nrf2-sMaf heterodimer function in cytoprotection. (2016)
  • Author(s): Otsuki A, Suzuki M, Katsuoka F, Tsuchida K, Suda H, Morita M, Shimizu R, Yamamoto M.
  • Journal Title: Free Radic Biol Med Volume: 91 Pages: 45-57
  • DOI: 10.1016/j.freeradbiomed.2015.12.005
  • Peer Reviewed
• [Journal Article] Rare variant discovery by deep whole-genome sequencing of 1070 Japanese Individuals (2015)
  • Author(s): Nagasaki M, Yasuda J, Katsuoka F, Nariai N, Kojima K, Kawai Y, Yamaguchi-Kabata Y, Yokozawa J, Danjoh I, Saito S, Sato Y, Mimori T, Tsuda K, Saito R, Pan X, Nishikawa S, Ito S, Kuroki Y, Tanabe O, Fuse N, Kuriyama S, Kiyomoto H, Hozawa A, Minegishi N, Engel J D, Kinoshita K, Kure S, Yaegashi N, Yamamoto M.
  • Journal Title: Nature Communications Volume: 6 Issue: 1 Pages: 8018-8018
  • DOI: 10.1038/ncomms9018
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] iJGVD: an integrative Japanese genome variation database based on whole-genome sequencing (2015)
  • Author(s): Yamaguchi-Kanata Y, Nariai N, Kawai Y, Sato Y, Kojima K, Tateno M, Katsuoka F, Yasuda J, Yamamoto M, Nagasaki M
  • Journal Title: Human Genome Variation Volume: 2 Issue: 1 Pages: 15050-15050
  • DOI: 10.1038/hgv.2015.50
  • Peer Reviewed
• [Journal Article] Adjustment of Cell-Type Composition Minimizes Systematic Bias in Blood DNA Methylation Profiles Derived by DNA Collection Protocols. (2015)
  • Author(s): Shiwa Y, Hachiya T, Furukawa R, Ohmomo H, Ono K, Kudo H, Hata J, Hozawa A, Iwasaki M, Matsuda K, Minegishi N, Satoh M, Tanno K, Yamaji T, Wakai K, Hitomi J, Kiyohara Y, Kubo M, Tanaka H, Tsugane S, Yamamoto M, Sobue K, Shimizu A.
  • Journal Title: PLoS ONE Volume: 6 Issue: 1 Pages: 8018-8018
  • DOI: 10.1371/journal.pone.0147519
  • Peer Reviewed / Open Access
• [Presentation] Processing, Storage and Management Systems of Cell Samples in TMM Biobank. (2018)
  • Author(s): Ishida N, Nobukuni T, Nishijima I, Kudo H, Yamashita R, Terakawa T, Yamamoto M, Minegishi N
  • Organizer: European Biobank Week
  • Int'l Joint Research
• [Presentation] Quality Management in TMM Biobank: Standardization Enhances Collaboration. (2018)
  • Author(s): Naoko Minegishi
  • Organizer: Workshop on Quality Control and Standardization of Biobanks and Biobanking
  • Int'l Joint Research / Invited
• [Presentation] Experience as the Public Population-Based Biobank in the Disaster- Stricken Areas in Japan (2017)
  • Author(s): Minegishi N, the Tohoku Medical Megabank Project Study Group
  • Organizer: The 2017 Japan-NIH Joint Symposium on Advances in Biomedical Research and Disease
  • Place of Presentation: Tohoku University (Sendai, Miyagi)
  • Year and Date: 2017-02-15
  • Int'l Joint Research / Invited
• [Presentation] 東北メディカル・メガバンク計画バイオバンクの保存試料とその利用について (2017)
  • Author(s): 峯岸直子
  • Organizer: 第24回クロマトグラフィーシンポジウム
  • Invited
• [Presentation] Baseline Collection and the 2nd Stage Activity of TMM Biobank (2017)
  • Author(s): Naoko Minegishi
  • Organizer: 第2回 カロリンスカ研究所・東北大学合同会議
  • Int'l Joint Research / Invited
• [Presentation] TMMバイオバンクの試料・情報利活用における課題 (2017)
  • Author(s): 峯岸直子
  • Organizer: 放射線影響研究所ワークショップ「生物試料を用いる共同研究で求められる倫理的配慮」
  • Invited
• [Presentation] TMM Biobank, an Integrated Population-Based Biobank, as a Part of the Reconstruction Project after Tsunami Disaster (2016)
  • Author(s): Minegishi N, Kudo H, Nobukuni T, Terakawa T, Suzuki S, Nishijima I, Ishida N, Yamashita, R Satoh M, Sasaki M, Yamamoto M and the Tohoku Medical Megabank Project Study Group
  • Organizer: Europe Biobank Week, Biobanking for Health Innovation
  • Place of Presentation: Vienna, Austria
  • Year and Date: 2016-09-13
  • Int'l Joint Research
• [Presentation] Reliability of ID Management in a Japanese Population-Based Biobank (2016)
  • Author(s): Kudo H, Nishijima I, Terakawa T, Nobukuni T, Ishida N, Yamashita R, Yamaguchi-Kabata Y, Kojima K, Saito S, Ogishima S, Katsuoka F, Nagasaki M, Yasuda J, Satoh M, Minegishi N, Sasaki M, Yamamoto M, the Tohoku Medical Megabank Project Study Group
  • Organizer: Europe Biobank Week, Biobanking for Health Innovation
  • Place of Presentation: Vienna, Austria
  • Year and Date: 2016-09-13
  • Int'l Joint Research
• [Presentation] TMM Biobank Preparing for the 2nd Stage Program (2016)
  • Author(s): Minegishi N, Kudo H, Yamashita R, Ishida N Terakawa T, Nishijima I, Nobukuni T
  • Organizer: NHRI-ToMMo Conference Genomics, Biobanking, and Medical informatics for Precision Medicine
  • Place of Presentation: Tohoku University (Sendai, Miyagi)
  • Year and Date: 2016-07-15
  • Int'l Joint Research
• [Presentation] 東北メディカル・メガバンクの目標と進捗状況について (2016)
  • Author(s): 峯岸直子
  • Organizer: 放射線影響研究所ワークショップ（厚生労働省：丹羽班研究） 生物試料の保存と活用
  • Place of Presentation: 放射線影響研究所（ 広島県広島市）
  • Year and Date: 2016-02-03
  • Invited
• [Presentation] 脳科学関連バイオリソースの整備・普及と調査研究-東北メディカル・メガバンクの現状と今後の展望 (2015)
  • Author(s): 峯岸直子
  • Organizer: 日本脳科学関連学会連合主催「脳科学の新しい推進プログラムに関する検討会」
  • Place of Presentation: 東京大学医学部 鉄門記念講堂（ 東京都文京区）
  • Year and Date: 2015-11-29
• [Presentation] The Biobank of Tohoku Medical Megabank Organization. (2015)
  • Author(s): Naoko Minegishi
  • Organizer: NHRI-ToMMo Conference, Genomics, biobanking, and Learning Health Systems 2015
  • Place of Presentation: Taipei, Taiwan
  • Year and Date: 2015-11-07
  • Int'l Joint Research / Invited
• [Presentation] Towards establishing a good biobanking system, survey on utilization of resources. (2015)
  • Author(s): Nobukuni T, Suzuki K, Ogishima S, Toda S, Kudo H, Nishijima I, Terakawa T, Arai T, Yamamoto M, Minegishi N.
  • Organizer: ESBB LONDON 2015
  • Place of Presentation: London UK
  • Year and Date: 2015-09-29
  • Int'l Joint Research
• [Presentation] Avilability of Records on Blood Collection and Transportation Influences Reliability of Omics Analysis. (2015)
  • Author(s): Saigusa D, Katoh Y, Koshiba S, Minegishi N , Kudo H, Nishijima I, Nobukuni T, Terakawa T, Tanabe O, Yamamoto M.
  • Organizer: HANDSON BIOBANK 2015
  • Place of Presentation: Milano, Italy
  • Year and Date: 2015-07-30
  • Int'l Joint Research
• [Presentation] Assessment of ID Integrity with ABO blood typing from Questionnaire to Genomic Data in Japanese Biobank: ToMMo (2015)
  • Author(s): Kudo H, Nishijima I, Terakawa T, Nobukuni T, Saito S, Ogishima S, Katsuoka F, Nagasaki M, Yasuda J, Minegishi N, Yamamoto M.
  • Organizer: ISBER (International Society for Biological and Environmental Repositories)2015 Annual meeting and exhibit
  • Place of Presentation: Phoenix, AZ, USA
  • Year and Date: 2015-05-05
  • Int'l Joint Research
• [Book] ヒト疾患のデータベースとバイオバンク 第２章 概論 疾患データベースとバイオバンクの現状と動向 (2017)
  • Author(s): 峯岸直子
  • Total Pages: 227
  • Publisher: 羊土社
  • ISBN: 9784758103664