• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to previous page

Pathogenic mechanisms of Cushing disease caused by gain-of-function USP8 mutations

Research Project

Project/Area Number 15H04293
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Tumor biology
Research InstitutionTokyo Institute of Technology

Principal Investigator

Komada Masayuki  東京工業大学, 科学技術創成研究院, 教授 (10225568)

Research Collaborator Fukushima Toshiaki  
Endo Akinori  
Kawaguchi Kohei  
Project Period (FY) 2015-04-01 – 2018-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥16,640,000 (Direct Cost: ¥12,800,000、Indirect Cost: ¥3,840,000)
Fiscal Year 2017: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2016: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2015: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
Keywordsユビキチン / 脱ユビキチン化酵素 / エンドサイトーシス / 受容体ダウンレギュレーション / 腫瘍 / クッシング病 / 脳下垂体 / ACTH / 遺伝子 / 蛋白質 / 酵素 / 細胞・組織 / シグナル伝達 / 医療・福祉 / 生理学 / 癌
Outline of Final Research Achievements

Cushing’s disease, one of intractable diseases, is caused by the hypersecretion of adrenocorticotropic hormone (ACTH) from pituitary tumors. In this study, we showed that the gene encoding deubiquitinating enzyme USP8 is frequently mutated in the pituitary tumors of Japanese Cushing’s disease patients. Mechanistically, the mutation induces the increased interaction of USP8 with ubiquitin-binding protein STAM, thereby enhancing USP8 enzyme activity. The mutated form of USP8 excessively deubiquitinates some membrane proteins including EGF receptor, vasopressin receptor V1b and somatostatin receptor SSTR2/5, and affects corticotroph proliferation and hormone secretion.

Academic Significance and Societal Importance of the Research Achievements

日本人Cushing病患者で高頻度にUSP8遺伝子に変異が起きているという今回の研究結果は、USP8変異によるCushing病の発症機構の詳細な解析が、わが国におけるCushing病の治療法を確立する上で非常に重要であることを示すものである。また、USP8の遺伝子変異がACTH産生細胞の増殖やホルモン産生に影響する分子メカニズムの一部が明らかとなったことは、未だに特効薬のないCushing病の治療にとって、治療薬開発のための分子基盤を示した成果だと言える。従って、本研究成果は、Cushing病の発症メカニズムの解明に貢献しただけではなく、治療薬開発にも役立つと考えられ、社会的意義は非常に高い。

Report

(4 results)
  • 2018 Final Research Report ( PDF )
  • 2017 Annual Research Report
  • 2016 Annual Research Report
  • 2015 Annual Research Report
  • Research Products

    (63 results)

All 2019 2018 2017 2016 2015 Other

All Int'l Joint Research (15 results) Journal Article (19 results) (of which Int'l Joint Research: 7 results,  Peer Reviewed: 12 results,  Open Access: 5 results,  Acknowledgement Compliant: 5 results) Presentation (20 results) (of which Int'l Joint Research: 3 results,  Invited: 4 results) Book (1 results) Remarks (8 results)

  • [Int'l Joint Research] カロリンスカ研究所/Lund大学(スウェーデン)

    • Related Report
      2017 Annual Research Report
  • [Int'l Joint Research] 応用科学アッパーオーストリア大学(オーストリア)

    • Related Report
      2017 Annual Research Report
  • [Int'l Joint Research] モナシュ大学(オーストラリア)

    • Related Report
      2017 Annual Research Report
  • [Int'l Joint Research] Medizinische Klinik und Poliklinik IV(ドイツ)

    • Related Report
      2016 Annual Research Report
  • [Int'l Joint Research] National Institute of Health(米国)

    • Related Report
      2016 Annual Research Report
  • [Int'l Joint Research] McGill University(カナダ)

    • Related Report
      2016 Annual Research Report
  • [Int'l Joint Research] University of Rome Tor Vergata(イタリア)

    • Related Report
      2016 Annual Research Report
  • [Int'l Joint Research] The University of Melbourne(オーストラリア)

    • Related Report
      2016 Annual Research Report
  • [Int'l Joint Research]

    • Related Report
      2016 Annual Research Report
  • [Int'l Joint Research] Medizinische Klinik und Poliklinik IV/Ludwig-Maximilians-Universitat Munchen/Max Planck Institute of Psychiatry(ドイツ)

    • Related Report
      2015 Annual Research Report
  • [Int'l Joint Research] National Institutes of Health/Oregon Health & Science University(米国)

    • Related Report
      2015 Annual Research Report
  • [Int'l Joint Research] Queen Mary University of London(英国)

    • Related Report
      2015 Annual Research Report
  • [Int'l Joint Research] Universite Paris Descartes(フランス)

    • Related Report
      2015 Annual Research Report
  • [Int'l Joint Research] Jiangsu Cancer Hospital(中国)

    • Related Report
      2015 Annual Research Report
  • [Int'l Joint Research]

    • Related Report
      2015 Annual Research Report
  • [Journal Article] RNA-seq of Isolated Chromaffin Cells Highlights the Role of Sex-Linked and Imprinted Genes in Adrenal Medulla Development.2019

    • Author(s)
      Chan Wing Hei, Komada Masayuki, Fukushima Toshiaki, Southard-Smith E. Michelle, Anderson Colin R., Wakefield Matthew J.
    • Journal Title

      Scientific Report

      Volume: 9(1) Issue: 1 Pages: 3929-3929

    • DOI

      10.1038/s41598-019-40501-0

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The integral function of the endocytic recycling compartment is regulated by RFFL-mediated ubiquitylation of Rab11 effectors2019

    • Author(s)
      Sakai R, Fukuda R, Unida S, Aki M, Ono Y, Endo A, Kusumi S, Koga D, Fukushima T, Komada M, Okiyoneda T
    • Journal Title

      J Cell Sci.

      Volume: 132 Issue: 3 Pages: 228007-228007

    • DOI

      10.1242/jcs.228007

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Ubiquitin-specific protease 8 deubiquitinates Sec31A and decreases large COPII carriers and collagen IV secretion2018

    • Author(s)
      Kawaguchi Kohei、Endo Akinori、Fukushima Toshiaki、Madoka Yuka、Tanaka Toshiaki、Komada Masayuki
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 499 Issue: 3 Pages: 635-641

    • DOI

      10.1016/j.bbrc.2018.03.202

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] IRS-2 deubiquitination by USP9X maintains anchorage-independent cell growth via Erk1/2 activation in prostate carcinoma cell line.2018

    • Author(s)
      Furuta Haruka, Yoshihara Hidehito, Fukushima Toshiaki, Yoneyama Yosuke, Ito Akihiro, Worrall Claire, Girnita Ada, Girnita Leonard, Yoshida Minoru, Asano Tomoichiro, Komada Masayuki, Kataoka Naoyuki, Chida Kazuhiro, Hakuno Fumihiko, Takahashi Shin-Ichiro
    • Journal Title

      Oncotarget

      Volume: 9(74) Issue: 74 Pages: 33871-33883

    • DOI

      10.18632/oncotarget.26049

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] USP15 attenuates IGF-I signaling by antagonizing Nedd4-induced IRS-2 ubiquitination.2017

    • Author(s)
      Fukushima T, Yoshihara H, Furuta H, Hakuno F, Iemura SI, Natsume T, Nakatsu Y, Kamata H, Asano T, Komada M, Takahashi SI.
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 484 Issue: 3 Pages: 522-528

    • DOI

      10.1016/j.bbrc.2017.01.101

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Tandem UIMs confer Lys48 ubiquitin chain substrate preference to deubiquitinase USP252017

    • Author(s)
      Kawaguchi K, Uo K, Tanaka T, Komada M
    • Journal Title

      Sci. Rep.

      Volume: 7 Issue: 1 Pages: 45037-45037

    • DOI

      10.1038/srep45037

    • NAID

      120006605589

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Deficiency of X-linked protein kinase Nrk during pregnancy triggers breast tumor in mice2016

    • Author(s)
      Yanagawa T, Denda K, Inatani T, Fukushima T, Tanaka T, Kumaki N, Inagaki Y, Komada M
    • Journal Title

      Am. J. Pathol.

      Volume: 186 Issue: 10 Pages: 2751-2760

    • DOI

      10.1016/j.ajpath.2016.06.005

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Ankrd13 family of ubiquitin-interacting motif-bearing proteins regulates VCP/p97-mediated lysosomal traffic of caveolin-1.2016

    • Author(s)
      Burana, D., Yoshihara, H., Tanno, H., Yamamoto, A., Saeki, Y., Tanaka, K., and Komada, M.
    • Journal Title

      J. Biol. Chem.

      Volume: 291 Issue: 12 Pages: 6218-6231

    • DOI

      10.1074/jbc.m115.710707

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] The USP8 mutational status may predict drug susceptibility in corticotroph adenomas of Cushing's disease.2016

    • Author(s)
      Hayashi, K., Inoshita, N., Kawaguchi, K., Ardisasmita, A.I., Suzuki, H., Fukuhara, N., Okada, M., Nishioka, H., Takeuchi, Y., Komada, M., Takeshita, A., and Yamada, S.
    • Journal Title

      Eur. J. Endocrinol.

      Volume: 174 Issue: 2 Pages: 213-226

    • DOI

      10.1530/eje-15-0689

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] クッシング病の原因遺伝子と発症機構.2016

    • Author(s)
      川口紘平、駒田雅之
    • Journal Title

      Annual Review 糖尿病・代謝・内分泌

      Volume: なし Pages: 180-186

    • Related Report
      2015 Annual Research Report
  • [Journal Article] 脱ユビキチン化酵素によるエンドサイトーシス制御と遺伝子疾患.2016

    • Author(s)
      川口紘平、駒田雅之
    • Journal Title

      医学のあゆみ

      Volume: 256 Pages: 861-867

    • Related Report
      2015 Annual Research Report
  • [Journal Article] The gene of the ubiquitin-specific protease 8 is frequently mutated in adenomas causing Cushing's disease.2015

    • Author(s)
      Perez-Rivas, L.G.,
    • Journal Title

      J. Clin. Endocrinol. Metab.

      Volume: 100 Issue: 7 Pages: E997-E1004

    • DOI

      10.1210/jc.2015-1453

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Decoding the genetic basis of Cushing's disease: USP8 in the spotlight.2015

    • Author(s)
      Theodoropoulou, M., Reincke, M., Fassnacht, M., and *Komada, M. (*co-correspondence)
    • Journal Title

      Eur. J. Endocrinol.

      Volume: 173 Issue: 4 Pages: M73-M83

    • DOI

      10.1530/eje-15-0320

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] The nucleolar ubiquitin-specific protease USP36 deubiquitinates and stabilizes c-Myc2015

    • Author(s)
      Sun XX, He X, Yin L, Komada M, Sears RC & Dai MS
    • Journal Title

      Proc. Natl. Acad. Sci. USA

      Volume: 112 Issue: 12 Pages: 3734-3739

    • DOI

      10.1073/pnas.1411713112

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] 脱ユビキチン化酵素USP8の機能獲得型変異はCushing病をひき起こす2015

    • Author(s)
      駒田 雅之
    • Journal Title

      ライフサイエンス新着論文レビュー ”First Author's"

      Volume: なし

    • Related Report
      2015 Annual Research Report
  • [Journal Article] 見えてきたユビキチンを介した核小体の多彩な機能2015

    • Author(s)
      川口 紘平、駒田 雅之
    • Journal Title

      ファルマシア

      Volume: 51 Pages: 300-304

    • Related Report
      2015 Annual Research Report
  • [Journal Article] 難病 ”クッシング病” 発症の分子メカニズム.2015

    • Author(s)
      川口 紘平、駒田 雅之
    • Journal Title

      バイオサイエンスとインダストリー

      Volume: 73 Pages: 300-301

    • Related Report
      2015 Annual Research Report
  • [Journal Article] 脱ユビキチン化酵素USP8変異とCushing病2015

    • Author(s)
      駒田 雅之
    • Journal Title

      クッシング症候群診療マニュアル

      Volume: なし Pages: 259-260

    • Related Report
      2015 Annual Research Report
  • [Journal Article] 脱ユビキチン化酵素USP8の機能獲得型変異がクッシング病を引き起こす2015

    • Author(s)
      駒田 雅之
    • Journal Title

      ACTH Related Peptides

      Volume: 26 Pages: 56-58

    • Related Report
      2015 Annual Research Report
  • [Presentation] 脱ユビキチン化酵素USP8の自己活性抑制機構2019

    • Author(s)
      柿原慧遵、 浅水謙吾、 遠藤彬則、 駒田雅之、福嶋俊明
    • Organizer
      第2回ユビキチン研究会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Nuclear localization mechanism of deubiquitinating enzyme USP8 in Cushing’s disease.2018

    • Author(s)
      Takahiro Sawada, Kazuya Inoko, Kohei Kawaguchi, Akinori Endo, Yasushi Saeki, Keiji Tanaka, Toshiaki Fukushima, Masayuki Komada
    • Organizer
      第41回日本分子生物学会年会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Molecular mechanisms underlying the control of Nrk protein levels and Nrk-mediated anti-proliferation effects.2018

    • Author(s)
      Satomi Naito, Akinori Endo, Toshiaki Fukushima, Kimitoshi Denda, Akira Kato, Masayuki Komada
    • Organizer
      第41回日本分子生物学会年会
    • Related Report
      2017 Annual Research Report
  • [Presentation] A deubiquitinase USP8, a master regulator of endosome-centered membrane traffic, controls inter-cellular signal transduction.2018

    • Author(s)
      Akinori Endo, Toshiaki Fukushima, Masayuki Komada
    • Organizer
      第41回日本分子生物学会年会
    • Related Report
      2017 Annual Research Report
  • [Presentation] USP8 遺伝子のゲノム編集によるCushing 病モデル細胞の作製と解析2018

    • Author(s)
      Suguru Machidori, Kazuya Inoko, Kohei Kawaguchi, Akinori Endo, Toshiaki Fukushima, Masayuki Komada
    • Organizer
      第33回日本下垂体研究会学術集会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Ubiquitin-specific protease 8 suppresses collagen secretion by deubiquitinating Sec31.2018

    • Author(s)
      Kohei Kawaguchi, Akinori Endo, Toshiaki Fukushima, Masayuki Komada
    • Organizer
      Cell and Developmental Biology Meeting
    • Related Report
      2017 Annual Research Report
  • [Presentation] Deubiquitinases USP5 and USP13 are recruited to and regulate heat-induced stress granules by deubiquitinating activities.2018

    • Author(s)
      Xie Xuan, Shunsuke Matsumoto, Akinori Endo, Toshiaki Fukushima, Hiroyuki Kawahara, Yasushi Saeki, Masayuki Komada
    • Organizer
      Cold Spring Harbor Asia Conferences, Ubiquitin Family, Autophagy and Diseases,
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] クッシング病において脱ユビキチン化酵素USP8変異体を活性化するプロテアーゼの解析2017

    • Author(s)
      浅水謙吾、川口紘平、遠藤彬則、福嶋俊明、金丸周司、駒田雅之
    • Organizer
      第28回 間脳・下垂体・副腎系研究会
    • Place of Presentation
      ロシュ・ダイアグノスティックス 本社ビル(東京都港区)
    • Related Report
      2016 Annual Research Report
  • [Presentation] 遺伝子変異による脱ユビキチン化酵素USP8の細胞質から核への局在変化とCushing病2016

    • Author(s)
      駒田雅之
    • Organizer
      第39回 日本分子生物学会大会
    • Place of Presentation
      パシフィコ横浜(神奈川県横浜市)
    • Year and Date
      2016-11-30
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] 母性Cyclin E-DNMT1新規複合体によるツメガエル尾部形成のエピジェネティックな制御2016

    • Author(s)
      田中利明、駒田雅之
    • Organizer
      第39回 日本分子生物学会大会
    • Place of Presentation
      パシフィコ横浜(神奈川県横浜市)
    • Year and Date
      2016-11-30
    • Related Report
      2016 Annual Research Report
  • [Presentation] クッシング病で見られる脱ユビキチン化酵素USP8の変異はバソプレシン受容体V1bの安定化を引き起こす2016

    • Author(s)
      福嶋俊明、川口紘平、遠藤彬則、駒田雅之
    • Organizer
      第39回 日本分子生物学会大会
    • Place of Presentation
      パシフィコ横浜(神奈川県横浜市)
    • Year and Date
      2016-11-30
    • Related Report
      2016 Annual Research Report
  • [Presentation] 脱ユビキチン化酵素USP28はSnailを安定化し、がん細胞の浸潤に寄与する2016

    • Author(s)
      佐藤晃一、井上靖道、伊藤友香、駒田雅之、林秀敏
    • Organizer
      第39回 日本分子生物学会大会
    • Place of Presentation
      パシフィコ横浜(神奈川県横浜市)
    • Year and Date
      2016-11-30
    • Related Report
      2016 Annual Research Report
  • [Presentation] Deubiquitinase USP5 is required for the disassembly of heat-induced stress granules2016

    • Author(s)
      Xuan Xie, Shunsuke Matsumoto, Masayuki Komada
    • Organizer
      第39回 日本分子生物学会大会
    • Place of Presentation
      パシフィコ横浜(神奈川県横浜市)
    • Year and Date
      2016-11-30
    • Related Report
      2016 Annual Research Report
  • [Presentation] 脱ユビキチン化酵素USP25のユビキチン結合モチーフはK48ユビキチン鎖に対する切断特異性を規定する2016

    • Author(s)
      川口紘平、卯尾和音、田中利明、駒田雅之
    • Organizer
      第39回 日本分子生物学会大会
    • Place of Presentation
      パシフィコ横浜(神奈川県横浜市)
    • Year and Date
      2016-11-30
    • Related Report
      2016 Annual Research Report
  • [Presentation] Cushing病におけるUSP8インタラクトーム解析2016

    • Author(s)
      駒田雅之
    • Organizer
      第43回 日本神経内分泌学会学術集会
    • Place of Presentation
      アクトシティ浜松コングレスセンター(静岡県浜松市)
    • Year and Date
      2016-10-14
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] USP8 interactome in Cushing’s disease2016

    • Author(s)
      Masayuki Komada
    • Organizer
      IMPROCUSH-2 (Improving Outcome of Cushing’s Syndrome Symposium 2)
    • Place of Presentation
      Carl Friedrich von Siemens Stiftung (Munich, Germany)
    • Year and Date
      2016-06-23
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 脱ユビキチン化酵素USP25におけるユビキチン結合モチーフUIMの機能2015

    • Author(s)
      卯尾和音、田中利明、駒田雅之
    • Organizer
      第38回 日本分子生物学会/第88回日本生化学会・合同大会 BMB2015
    • Place of Presentation
      神戸ポートアイランド
    • Year and Date
      2015-12-02
    • Related Report
      2015 Annual Research Report
  • [Presentation] 脱ユビキチン化酵素USP37におけるユビキチン結合モチーフUIMの機能2015

    • Author(s)
      西川周平、桑原直之、伝田公紀、川崎政人、駒田雅之、加藤龍一
    • Organizer
      第38回 日本分子生物学会/第88回 日本生化学会・合同大会 BMB2015
    • Place of Presentation
      神戸ポートアイランド
    • Year and Date
      2015-12-02
    • Related Report
      2015 Annual Research Report
  • [Presentation] 脳下垂体の腫瘍性疾患クッシング病における脱ユビキチン化酵素USP8の活性化変異2015

    • Author(s)
      駒田雅之、川口紘平、Arif Ibrahim Ardisasmita、福嶋俊明
    • Organizer
      第38回 日本分子生物学会/第88回 日本生化学会・合同大会 BMB2015
    • Place of Presentation
      神戸ポートアイランド
    • Year and Date
      2015-12-01
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] Somatic gain-of-function mutations in deubiquitinase USP8 in pituitary tumors causing Cushing's disease2015

    • Author(s)
      駒田雅之
    • Organizer
      EMBO Conference on “Ubiquitin and Ub-like modifiers”
    • Place of Presentation
      Hotel Croatia(クロアチア・ツァブタット)
    • Year and Date
      2015-09-19
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Book] Encyclopedia of Signaling Molecules, 2nd Edition2017

    • Author(s)
      Komada M, Reincke M, Theodoropoulou M
    • Total Pages
      4700
    • Publisher
      Springer
    • Related Report
      2016 Annual Research Report
  • [Remarks] 東京工業大学 科学技術創成研究院 細胞制御工学研究センター 駒田研究室

    • URL

      https://komada-lab.jimdo.com/

    • Related Report
      2017 Annual Research Report
  • [Remarks] 駒田研究室 ホームページ

    • URL

      http://www.komada-lab.bio.titech.ac.jp

    • Related Report
      2016 Annual Research Report
  • [Remarks] 細胞制御工学研究センター ホームページ

    • URL

      http://www.rcb.iir.titech.ac.jp

    • Related Report
      2016 Annual Research Report
  • [Remarks] 科学技術創成研究院 ホームページ

    • URL

      http://www.iir.titech.ac.jp

    • Related Report
      2016 Annual Research Report
  • [Remarks] 生命理工学院 ホームページ

    • URL

      http://www.educ.titech.ac.jp/bio/

    • Related Report
      2016 Annual Research Report
  • [Remarks] 東京工業大学 ホームページ

    • URL

      http://www.titech.ac.jp

    • Related Report
      2016 Annual Research Report
  • [Remarks] 東京工業大学 科学技術創成研究院 駒田研究室 ホームページ

    • URL

      http://www.komada-lab.bio.titech.ac.jp

    • Related Report
      2015 Annual Research Report
  • [Remarks] 科研費 新学術領域 ユビキチン制御 ホームページ

    • URL

      http://www.ubiquitin.jp

    • Related Report
      2015 Annual Research Report

URL: 

Published: 2015-04-16   Modified: 2022-09-26  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi