Elucidation of regulatory mechanism to maintain genome stability by novel BRCA1-interacting molecules and development of cancer therapy
| Project/Area Number |
16H04690
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Tumor biology
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| Research Institution | Tohoku University |
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Principal Investigator |
CHIBA Natsuko 東北大学, 加齢医学研究所, 教授 (50361192)
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| 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)
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| 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)
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| Keywords | BRCA1 / 中心体 / ゲノム安定性維持 / 細胞分裂 / がん関連分子 / がん / 癌 |
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| 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.
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| 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。
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Report
(4 results)
Research Products
(31 results)
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[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.
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Journal Title
Oncogene
Volume: 印刷中
Pages: 3077-3092
DOI
Related Report
Peer Reviewed
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[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.
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Journal Title
Molecular Cancer Research
Volume: 6(10)
Pages: 1499-1511
DOI
Related Report
Peer Reviewed / Open Access
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[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.
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Journal Title
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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