Elucidation of novel functions of GRWD1, a multifunctional protein with histone chaperone activity

• Project/Area Number: 25291027
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Functional biochemistry
• Research Institution: Kyushu University
• Principal Investigator: Fujita Masatoshi 九州大学, 薬学研究科(研究院), 教授 (30270713)
• Project Period (FY): 2013-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥17,940,000 (Direct Cost: ¥13,800,000、Indirect Cost: ¥4,140,000); Fiscal Year 2016: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2015: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2014: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2013: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
• Keywords: 新規がん遺伝子 / 新規がん診断法 / GRWD1 / p53 / RPL11 / MDM2 / がん遺伝子 / 核小体ストレス / Ribosomal protein / ヒストンシャペロン / EDD / Pura / 転写 / EDDユビキチンリガーゼ / RP / リボソーム蛋白質

Outline of Final Research Achievements

Here, we show that GRWD1 is a novel oncogene that negatively regulates p53 via the RPL11-MDM2 and RPL23-MDM2 pathways. Furthermore, analyses of several cancer databases reveal that high expression of GRWD1 is associated with poor prognosis of patients suffering from certain cancers. It will become a useful diagnostic method for certain cancers to test the expression levels of GRWD1 in clinical samples. If novel compounds that can interfere with the interaction between GRWD1 and RPL11 (or RPL23) will be identified, they will be powerful novel anti-neoplastic agents.

Research Products

• [Journal Article] GRWD1 negatively regulates p53 via the RPL11-MDM2 pathway and promotes tumorigenesis. (2017)
  • Author(s): Kayama K, Watanabe S, Takafuji T, Tsuji T, Hironaka K, Matsumoto M, Nakayama KI, Enari M, Kohno T, Shiraishi K, Kiyono T, Yoshida K, Sugimoto N, Fujita M.
  • Journal Title: EMBO Rep. Volume: 18 Issue: 1 Pages: 123-137
  • DOI: 10.15252/embr.201642444
  • Peer Reviewed
• [Journal Article] TRF2 recruits ORC through TRFH domain dimerization. (2017)
  • Author(s): Higa M. et al.
  • Journal Title: Biochim. Biophys. Acta Volume: 1864 Issue: 1 Pages: 191-201
  • DOI: 10.1016/j.bbamcr.2016.11.004
  • Peer Reviewed
• [Journal Article] Nucleosome assembly and disassembly activity of GRWD1, a novel Cdt1-binding protein that promotes pre-replication complex formation. (2016)
  • Author(s): Aizawa M et al.
  • Journal Title: Biochim. Biophys. Acta Volume: 1863 Issue: 11 Pages: 2739-2748
  • DOI: 10.1016/j.bbamcr.2016.08.008
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Cdt1-binding protein GRWD1 is a novel histone-binding protein that facilitates MCM loading through its influence on chromatin architecture. (2015)
  • Author(s): Sugimoto N, Maehara K, Yoshida K, Yasukouchi S, Osano S, Watanabe S, Aizawa M, Yugawa T, et al.
  • Journal Title: Nucleic Acids Res. Volume: 43 Issue: 12 Pages: 5898-5911
  • DOI: 10.1093/nar/gkv509
  • Peer Reviewed / Open Access
• [Journal Article] ATM regulates Cdt1 stability during the unperturbed S phase to prevent re-replication. (2014)
  • Author(s): Iwahori S, Kohmon D, Kobayashi J, Tani Y, Yugawa T, Komatsu K, Kiyono T, Sugimoto N, Fujita M.
  • Journal Title: Cell Cycle Volume: 13 Issue: 3 Pages: 471-481
  • DOI: 10.4161/cc.27274
  • Peer Reviewed / Open Access
• [Journal Article] Noncanonical NOTCH signaling limits self-renewal of human epithelial and induced pluripotent stem cells through ROCK activation. (2013)
  • Author(s): Yugawa T, Nishino K, Ohno S, Nakahara T, Fujita M, Goshima N, Umezawa A, Kiyono T
  • Journal Title: Molecular and Cellular Biology Volume: 33(22) Issue: 22 Pages: 4434-4447
  • DOI: 10.1128/mcb.00577-13
  • Peer Reviewed
• [Presentation] GRWD1によるp53転写活性化能の抑制機構の解明 (2016)
  • Author(s): 廣中研介ら
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-11-30
• [Presentation] GRWD1は核小体ストレス誘導因子RPL23タンパク質量を制御している (2016)
  • Author(s): 渡邉心也ら
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-11-30
• [Presentation] GRWD1 counteracts p53 via the RPL11-MDM2 pathway and promotes tumorigenesis (2016)
  • Author(s): Fujita M. et al.
  • Organizer: 10th 3R International Symposium
  • Place of Presentation: ホテル一畑（松江市）
  • Year and Date: 2016-11-13
  • Int'l Joint Research
• [Presentation] GRWD1はRPL11-MDM2経路を介してp53を抑制し細胞がん化を促進する (2016)
  • Author(s): 藤田雅俊ら
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-10-06
• [Presentation] ヒト細胞におけるpre-RC形成とfiringの時空間的制御のゲノムワイド解析 (2015)
  • Author(s): 杉本のぞみら
  • Organizer: 第３８回日本分子生物学会年会／第８８回日本生化学会大会 合同大会
  • Place of Presentation: 神戸ポートアイランド
  • Year and Date: 2015-12-01
  • Invited
• [Presentation] GRWD1 のヌクレオソーム形成活性及び崩壊活性の解析 (2015)
  • Author(s): 會澤誠大ら
  • Organizer: 第２３回DNA複製・組換え・修復ワークショップ
  • Place of Presentation: 焼津グランドホテル
  • Year and Date: 2015-10-19
• [Presentation] GRWD1 negatively regulates p53 via the RP (ribosomal protein)-MDM2 pathway and promotes anchorage-independent growth (2015)
  • Author(s): 嘉山皓太ら
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋国際センター
  • Year and Date: 2015-10-08
• [Presentation] GRWD1による核小体ストレス応答RP-MDM2-p53経路の制御 (2014)
  • Author(s): 嘉山皓太
  • Organizer: 第37回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2014-11-25 – 2014-11-27
  • Invited
• [Presentation] GRWD1は核小体ストレス誘導因子RPL23タンパク質量を制御している (2014)
  • Author(s): 渡邉心也ら
  • Organizer: 第37回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2014-11-25 – 2014-11-27
• [Presentation] 新規ヒストンシャペロンGRWD1によるp53機能抑制 (2014)
  • Author(s): 都地崇拡ら
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Cdt1結合蛋白質GRWD1はクロマチン構造およびMCMローディングを制御する新規ヒストンシャペロンである (2013)
  • Author(s): 杉本のぞみ et al.
  • Organizer: 第65回日本細胞生物学会大会・シンポジウム
  • Place of Presentation: ウインク愛知
  • Invited
• [Presentation] Cdt1結合蛋白質GRWD1は新規ヒストンシャペロンでありクロマチン構造とMCM結合を制御している (2013)
  • Author(s): 杉本のぞみ et al.
  • Organizer: 第36回日本分子生物学会年会・ワークショップ
  • Place of Presentation: 神戸ポートアイランド
  • Invited
• [Presentation] 新規結合タンパク質の解析によるGRWD1の転写における機能解明 (2013)
  • Author(s): 都地崇拡 et al.
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 神戸ポートアイランド
• [Presentation] Cdt1-Binding Protein GRWD1 Is a Novel Histone Chaperone That Regulates Chromatin Structure and MCM Loading (2013)
  • Author(s): Sugimoto N., et al.
  • Organizer: Cold Spring Harbor Laboratory Meeting on "Eukaryotic DNA replication & Genome Maintenance"
  • Place of Presentation: Cold Spring Harbor, NY, USA
• [Remarks] ようこそ医薬細胞生化学研究室へ
  • URL: http://tansaku.phar.kyushu-u.ac.jp/saito/top.html
• [Remarks] ようこそ医薬細胞生化学研究室へ
  • URL: http://tansaku.phar.kyushu-u.ac.jp/saito/top.html