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Elucidation of regulatory mechanism to maintain genome stability by novel BRCA1-interacting molecules and development of cancer therapy

Research Project

Project/Area Number 16H04690
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Tumor biology
Research InstitutionTohoku University

Principal Investigator

CHIBA Natsuko  東北大学, 加齢医学研究所, 教授 (50361192)

Co-Investigator(Kenkyū-buntansha) 城田 松之  東北大学, 医学系研究科, 講師 (00549462)
渡邊 利雄  奈良女子大学, 自然科学系, 教授 (60201208)
吉野 優樹  東北大学, 加齢医学研究所, 助教 (60755700)
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥16,770,000 (Direct Cost: ¥12,900,000、Indirect Cost: ¥3,870,000)
Fiscal Year 2018: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
Fiscal Year 2017: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2016: ¥9,490,000 (Direct Cost: ¥7,300,000、Indirect Cost: ¥2,190,000)
KeywordsBRCA1 / 中心体 / ゲノム安定性維持 / 細胞分裂 / がん関連分子 / がん / 癌
Outline of Final Research Achievements

BRCA1 is a tumor suppressor that is associated with hereditary breast and ovarian cancer. BRCA1 functions in DNA repair together with BARD1, a heterodimer partner of BRCA1. We identified BRCA1-interacting proteins, OLA1 and RACK1 and analyzed their function. OLA1 and RACK1 directly bound to BRCA1, and BARD1, localized the centrosomes, and functioned in the regulation of the centrosome duplication. RACK1 was involved in centrosomal localization of BRCA1. Abnormal level of the expression of OLA1 or RACK1 caused dysregulation of centrosome duplication. Cancer-derived variants of BRCA1, BARD1, OLA1, and RACK1 abolished their interaction and function in centrosome duplication. These results elucidated the novel regulatory mechanism by BRCA1 to maintain genome stability.

Academic Significance and Societal Importance of the Research Achievements

BRCA1のがん抑制能として、これまでは核内での機能である、DNA二本鎖切断修復能が注目されてきたが、本研究により、BRCA1が中心体複製制御において重要な機能を果たし、その機能破綻が中心体数の異常を引き起こすことが明らかになった。中心体は微小管形成中心として機能し、分裂期には紡錘体極となり、娘細胞への均等な染色体分配を担う細胞内小器官で、ゲノム安定性に重要な機能を担っている。よって、中心体制御能もBRCA1の重要ながん抑制能であると考えられた。本研究成果は遺伝性乳がんの遺伝子診断の病的意義の不明なバリアントの病的意義の解明や、中心体を標的とした新しいがん治療法の開発に貢献できると考えられる。

Report

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

Research Products

(31 results)

All 2019 2018 2017 2016 Other

All Int'l Joint Research (4 results) Journal Article (8 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 8 results,  Open Access: 5 results,  Acknowledgement Compliant: 1 results) Presentation (18 results) (of which Int'l Joint Research: 3 results,  Invited: 3 results) Remarks (1 results)

  • [Int'l Joint Research] オハイオ州立大学(米国)

    • Related Report
      2018 Annual Research Report
  • [Int'l Joint Research] BARD1ライフサイエンス(オーストラリア)

    • Related Report
      2018 Annual Research Report
  • [Int'l Joint Research] オハイオ州立大学(U.S.A.)

    • Related Report
      2017 Annual Research Report
  • [Int'l Joint Research] BARD1ライフサイエンス(オーストラリア)

    • Related Report
      2017 Annual Research Report
  • [Journal Article] RACK1 regulates centriole duplication by controlling localization of BRCA1 to the centrosome in mammary tissue-derived cells.2019

    • Author(s)
      Yoshino Y, Qi H, Kanazawa R, Sugamata M, Suzuki K, Kobayshi A, Shindo K, Matsuzawa A, Shibata S, Endo S, Miyanishi Y, Shimaoka T, Ishioka C, Kanno S, Yasui A, and Chiba N.
    • Journal Title

      Oncogene

      Volume: 印刷中 Pages: 3077-3092

    • DOI

      10.1038/s41388-018-0647-8

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 1.Increased centrosome number in BRCA-related breast cancer specimens determined by immunofluorescence analysis.2018

    • Author(s)
      Watanabe G, Chiba N, Nomizu T, Furuta A, Sato K, Miyashita M, Tada H, Suzuki A, Ohuchi N, Ishida T.
    • Journal Title

      Cancer Science

      Volume: in press Pages: 2027-2035

    • DOI

      10.1111/cas.13595

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Loss of protein phosphatase 6 in mouse keratinocytes enhances K-ras G12D -driven tumor promotion2018

    • Author(s)
      Kurosawa Koreyuki、Inoue Yui、Kakugawa Yoichiro、Yamashita Yoji、Kanazawa Kosuke、Kishimoto Kazuhiro、Nomura Miyuki、Momoi Yuki、Sato Ikuro、Chiba Natsuko、Suzuki Mai、Ogoh Honami、Yamada Hidekazu、Miura Koh、Watanabe Toshio、Tanuma Nobuhiro、Tachi Masahiro、Shima Hiroshi
    • Journal Title

      Cancer Science

      Volume: 109 Pages: 2178-2187

    • DOI

      10.1111/cas.13638

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] BRCA1-interacting protein OLA1 requires interaction with BARD1 to regulate centrosome number.2018

    • Author(s)
      Yoshino Y, Qi H, Fujita H, Shirota M, Abe S, Komiyama Y, Shindo K, Nakayama M, Matsuzawa A, Kobayashi A, Ogoh H, Watanabe T, Ishioka C and Chiba N.
    • Journal Title

      Molecular Cancer Research

      Volume: 6(10) Pages: 1499-1511

    • DOI

      10.1158/1541-7786.mcr-18-0269

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Increased centrosome number in BRCA-related breast cancer specimens determined by immunofluorescence analysis2018

    • Author(s)
      Gou Watanabe, Natsuko Chiba, Tadashi Nomizu, Akihiko Furuta, Kaolu Sato, Minoru Miyashita, Hiroshi Tada, Akihiko Suzuki, Noriaki Ohuchi, Takanori Ishida
    • Journal Title

      Cancer Science

      Volume: 印刷中

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Efficacy and safety of gemcitabine plus docetaxel in Japanese patients with unresectable or recurrent bone and soft tissue sarcoma: Results from a single-institutional analysis.2017

    • Author(s)
      Takahashi M, Komine K, Imai H, Okada Y, Saijo K, Takahashi M, Shirota H, Ohori H, Takahashi S, Chiba N, Mori T, Shimodaira H, Ishioka C.
    • Journal Title

      PLoS One

      Volume: 12(5)

    • DOI

      10.1371/journal.pone.0176972

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] ΔNp63α induces quiescence and downregulates the BRCA1 pathway in estrogen receptor-positive luminal breast cancer cell line MCF7 but not in other breast cancer cell lines.2016

    • Author(s)
      Amin R, Morita-Fujimura Y, Tawarayama H, Semba K, Chiba N, Fukumoto M, Ikawa S
    • Journal Title

      Molecular Oncology

      Volume: 10 Pages: 575-593

    • DOI

      10.1016/j.molonc.2015.11.009

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed
  • [Journal Article] OLA1 gene sequencing in patients with BRCA1/2 mutation-negative suspected hereditary breast and ovarian cancer.2016

    • Author(s)
      Takahashi M*, Chiba N*, Shimodaira H, Yoshino Y, Mori T, Sumii M, Nomizu T, Ishioka C.
    • Journal Title

      Breast Cancer

      Volume: 24(2) Pages: 336-340

    • DOI

      10.1007/s12282-016-0709-0

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Presentation] Function of BRCA1-interacting proteins OLA1 and BIP in centrosome and carcinogenesis2018

    • Author(s)
      Yuki Yoshino, Huicheng Qi, Kei Otsuka, and Natsuko Chiba
    • Organizer
      BASSER CENTER FOR BRCA 6th Annual Scientific Symposium BRCA1, BRCA2 and Beyond: An Update on hereditary Cancer
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] BRCA1結合分子BIP2の過剰発現はPLK1とAurora Aの活性化により中心体過剰複製を引き起こす2018

    • Author(s)
      小林輝大, 吉野優樹, 千葉奈津子
    • Organizer
      第77回日本癌学会学術総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 中心体制御における新規BRCA1結合因子OLA1とBARD1の相互作用の重要性2018

    • Author(s)
      吉野優樹, 齋匯成, 藤田拡樹, 小林輝大, 千葉奈津子.
    • Organizer
      第77回日本癌学会学術総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 新規BRCA1結合分子RACK1 の中心体複製制御能2018

    • Author(s)
      吉野優樹, 齋匯成, 小林輝大, 遠藤栞乃, 方震宙, 千葉奈津子.
    • Organizer
      第36回染色体ワークショップ 第17回核ダイナミクス研究会
    • Related Report
      2018 Annual Research Report
  • [Presentation] BRCA1結合分子OLA1の中心体のDNA損傷応答における機能2017

    • Author(s)
      齋匯成, 方震宙, 新藤一葉, 吉野優樹, 千葉奈津子.
    • Organizer
      第34回染色体ワークショップ
    • Place of Presentation
      木更津
    • Year and Date
      2017-01-11
    • Related Report
      2016 Annual Research Report
  • [Presentation] BRCA1結合分子OLA1による中心体のDNA損傷応答機構の解明2017

    • Author(s)
      齋匯成, 吉野優樹, 方震宙,千葉奈津子.
    • Organizer
      第69回日本細胞生物学会大会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 新規中心体制御因子RACK1によるBRCA1中心体局在制御と発がん2017

    • Author(s)
      吉野優樹, 小林輝大, 菅股眞美, 早坂美月, 齋匯成, 千葉奈津子.
    • Organizer
      第69回日本細胞生物学会大会
    • Related Report
      2017 Annual Research Report
  • [Presentation] BRCA1 supresses centrosome amplification induced by BIP2 over-expression in mammary epithelial cells.2017

    • Author(s)
      Shino Endo, Yuki Yoshino, Akihiro Kobayashi, Qi Huicheng, Natsuko Chiba.
    • Organizer
      第75回日本癌学会学術総会
    • Related Report
      2017 Annual Research Report
  • [Presentation] BRCA1-interacting protein OLA1 regulates centrosome amplification induced by DNA damage2017

    • Author(s)
      Huicheng Qi, Yuki Yoshino, Natsuko Chiba.
    • Organizer
      生命科学系学会合同年次大会 ConBio2017
    • Related Report
      2017 Annual Research Report
  • [Presentation] BRCA1の新規結合分子Ola1のノックアウトマウスの表現型の解析.2017

    • Author(s)
      吉田貴大, 吉野優樹, 小河穂波, 佐々木伯大, 中村保宏, 渡邊利雄, 千葉奈津子.
    • Organizer
      生命科学系学会合同年次大会 ConBio2017
    • Related Report
      2017 Annual Research Report
  • [Presentation] DNA損傷後の中心体数の増加のメカニズムの解明.2017

    • Author(s)
      斉匯成, 大橋和音, 方震宙, 吉野優樹, 千葉奈津子.
    • Organizer
      第34回染色体ワークショップ 第15回核ダイナミクス研究会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Function of the novel BRCA1-interacting protein OLA1 in centrosomal regulation and carcinogenesis.2017

    • Author(s)
      Yuki Yoshino, Huicheng Qi, Natsuko Chiba.
    • Organizer
      2nd Global Onsight Conference on Breast Cancer
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] BRCA1-interacting protein OLA1 is involved in the centrosomal duplication and response to DNA damage.2017

    • Author(s)
      Huicheng Qi, Kazune Ohashi, Fang Zhenzhou, Yuki Yoshino, Natsuko Chiba.
    • Organizer
      The 33rd International Symposium of Radiation Biology Center, Kyoto University
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 遺伝性乳がん・卵巣がんの現状と今後の展望2016

    • Author(s)
      千葉奈津子
    • Organizer
      第75回日本癌学会学術総会
    • Place of Presentation
      横浜
    • Year and Date
      2016-10-06
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] 中心体制御因子としての新規BRCA1結合因子BIP2の同定2016

    • Author(s)
      吉野優樹, 齋匯成, 石岡千加史, 安井明, 千葉奈津子.
    • Organizer
      第75回日本癌学会学術総会
    • Place of Presentation
      横浜
    • Year and Date
      2016-10-06
    • Related Report
      2016 Annual Research Report
  • [Presentation] 新規中心体タンパク質BIP2はBRCA1の中心体局在制御に関与する2016

    • Author(s)
      新藤一葉, 吉野優樹, 齋匯成, 菅股眞美, 早坂美月, 千葉奈津子.
    • Organizer
      第89回日本生化学会大会
    • Place of Presentation
      仙台
    • Year and Date
      2016-09-25
    • Related Report
      2016 Annual Research Report
  • [Presentation] BRCA1依存性に中心体数を制御する新規中心体タンパク質BIP2の同定2016

    • Author(s)
      吉野優樹, 齋匯成, 菅股眞美, 安井明, 千葉奈津子.
    • Organizer
      第89回日本生化学会大会
    • Place of Presentation
      仙台
    • Year and Date
      2016-09-25
    • Related Report
      2016 Annual Research Report
  • [Presentation] 新規中心体タンパク質BIP2はBRCA1の中心体局在と発がん機構に関与する2016

    • Author(s)
      齋匯成, 吉野優樹, 石岡千加史, 千葉奈津子.
    • Organizer
      第75回日本癌学会学術総会
    • Place of Presentation
      横浜
    • Year and Date
      2016-09-25
    • Related Report
      2016 Annual Research Report
  • [Remarks] 東北大学加齢医学研究所 腫瘍生物学分野

    • URL

      http://www2.idac.tohoku.ac.jp/dep/cab/

    • Related Report
      2018 Annual Research Report 2017 Annual Research Report

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Published: 2016-04-21   Modified: 2020-03-30  

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