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Study of DNA repair mechanisms that affect chemosensitivity of breast cancer

Research Project

Project/Area Number 18591446
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field General surgery
Research InstitutionSt.Marianna University School of Medicine

Principal Investigator

OHTA Tomohiko  St.Marianna University School of Medicine, Department of Surgery, Associate Professor (60233136)

Project Period (FY) 2006 – 2007
Project Status Completed (Fiscal Year 2007)
Budget Amount *help
¥3,980,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥480,000)
Fiscal Year 2007: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2006: ¥1,900,000 (Direct Cost: ¥1,900,000)
KeywordsBRCA1 / BARD1 / familial breast cancer / ubiquitin ligase / Nucleophosmin / RING finger / RPB8 / Nucleophosmin
Research Abstract

I have investigated the role of substrate ubiquitination by the breast and ovarian tumor suppressor BRCA1 on DNA damage response to elucidate the DNA damage repair mechanisms underlying chemosensitivity of breast cancer I previously identified several substrates including nucleophosmin (NPM1/B23) and RPB8, a common subunit of RNA polymerases. I have mainly investigated RPB8 in 2006 and found that 1) endogenous RPB8 interacts with BARD1, 2) RPB8 polyubiquitination by purified BRCAl-BARD1 in vitro, 3) Lys6-linked ubiquitin polymer formation in the RPB8 ubiquitination, 4) inhibition of in vivo RPB8 ubiquitination after UV irradiation by siRNA knockdown of BRCA1, 5) destabilization of endogenous RPB8 protein in vivo by siRNA knockdown of BRCA1, 6) HeLa cell lines stably expressing a ubiquitin-resistant form of RPB8 exhibited UV hypersensitivity accompanied by up-regulated caspase activity and p53 phosphorylation at Ser15. In 2006 I have mainly investigated NPM1. I established a cell lines stably expressing NPM1 mutant that is incapable of being ubiquitinated by BRCA1 and investigated its biological significance. However I finally concluded that the cells did not express the phenotype caused by the deficiency of the ubiquitination. I then reconstituted an in vitro NPM1 ubiquitination system using only purified recombinant proteins to investigate the effect of NPM1 ubiquitination on histone chaperone activity of NPM1. I further created recombinant proteins including NPM1, BRCA1-BARD1 heterodimer, Ube2w, Ubc13, and Mms2 and established Lys63-linked NPM1 polyubiquitination system to study DNA damage response.

Report

(3 results)
  • 2007 Annual Research Report   Final Research Report Summary
  • 2006 Annual Research Report
  • Research Products

    (45 results)

All 2008 2007 2006

All Journal Article (27 results) (of which Peer Reviewed: 12 results) Presentation (16 results) Patent(Industrial Property Rights) (2 results) (of which Overseas: 2 results)

  • [Journal Article] Involvement of kinesin family member 2C/mitotic centromere-associated kinesin overexpression in mammary carcinogenesis2008

    • Author(s)
      Arata S, et. al.
    • Journal Title

      Cancer Sci. 99(1)

      Pages: 62-70

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] The ubiquitin E3 ligase activity of BRCA1 and its biological functions2008

    • Author(s)
      Wenwen W, et. al.
    • Journal Title

      Cell Div. 7(3)

      Pages: 1-1

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] The ubiquitin E3 ligase activity of BRCA1 and its biological functions.2008

    • Author(s)
      Wu W, Koike A, Takeshita T, Ohta T.
    • Journal Title

      Cell Div. Jan 7

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Involvement of kinesin family member 2C/mitotic centromere-associated kinesin overexpression in mammary carcinogenesis.2008

    • Author(s)
      Shimo A, Tanikawa C, Nishidate T, Lin ML, Matsuda K, Park JH, Ueki T, Ohta T, Hirata K, Fukuda M, Nakamura Y, Katagiri T.
    • Journal Title

      Cancer Sci. 99(1)

      Pages: 62-70

    • NAID

      10024000927

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] The ubiquitin E3 ligase activity of BRCA1 and its biological functions.2008

    • Author(s)
      Wenwen Wu, et. al.
    • Journal Title

      Cell Div. 7(3)

      Pages: 1-1

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] BRCA1 ubiquitinates RPB8 in response to DNA damage2007

    • Author(s)
      Wenwen Wu, et. al.
    • Journal Title

      Cancer Res. 67(3)

      Pages: 951-958

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Elevated expression of PRC1,involved in the growth of breast cancer cells2007

    • Author(s)
      Arata S, et. al.
    • Journal Title

      Cancer Sci. 98

      Pages: 174-181

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Cytoplasmic destruction of p53 by the endoplasmic reticulum-resident ubiquitin ligase 'Synoviolin'2007

    • Author(s)
      Satoshi Y, et. al.
    • Journal Title

      EMBO J. 26

      Pages: 113-122

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Putative tumor suppressor EDD interacts with and up-regulates APC2007

    • Author(s)
      Ryuichi O, et. al.
    • Journal Title

      Genes Cells. 12(12)

      Pages: 1339-1345

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Modification of the Hepatic Mitochondrial Proteome in Response to Ischemic Preconditioning following Ischemia-Reperfusion Injury of the Rat Liver2007

    • Author(s)
      Ryuichi O, et. al.
    • Journal Title

      Eur Surg Res. 40(3)

      Pages: 247-255

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] 治療効果予測マーカー-最近のトピック、Basal-like乳癌に焦点をあてて-2007

    • Author(s)
      小池 彩華, 他
    • Journal Title

      日本臨床 65(sup.6)

      Pages: 285-290

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Putative tumor suppressor EDD interacts with and up-regulates APC.2007

    • Author(s)
      Ohshima R, Ohta T, Wu W, Koike A, Iwatani T, Henderson M, Watts CK, Otsubo T.
    • Journal Title

      Genes Cells. 12(12)

      Pages: 1339-45

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Modification of the Hepatic Mitochondrial Proteome in Response to Ischemic Preconditioning following Ischemia-Reperfusion Injury of the Rat Liver.2007

    • Author(s)
      Oshima R, Nakano H, Katayama M, Sakurai J, Wu W, Koizumi S, Asano T, Watanabe T, Asakura T, Ohta T, Otsubo T.
    • Journal Title

      Eur Surg Res. 40(3)

      Pages: 247-255

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Predictive markers in breast cancer treatment-focusing on a recent topicbasal-like breast cancer2007

    • Author(s)
      Koike A, Ohta T.
    • Journal Title

      Nippon Rinsho.(Suppl 6) 65

      Pages: 285-90

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] BRCA1 ubiquitinates RPB8 in response to DNA damage.2007

    • Author(s)
      Wu W, Nishikawa H, Hayami R, Sato K, Honda A, Aratani S, Nakajima T, Fukuda M, Ohta T.
    • Journal Title

      Cancer Res. 67(3)

      Pages: 951-8

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Elevated expression of PRC1, involved in the growth of breast cancer cells.2007

    • Author(s)
      Shimo A, Nishidate T, Ohta T, Fukuda M, Nakamura Y, Katagiri T.
    • Journal Title

      Cancer Sci. 98

      Pages: 174-81

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] 「研究成果報告書概要(欧文)」より2007

    • Author(s)
      Yamasaki S, Yagishita N, Sasaki T, Nakazawa M, Kato Y, Yamadera T, Bae E, Toriyama S, Ikeda R, Zhang L, Fujitani K, Yoo E, Tsuchimochi K, Ohta T, Araya N, Fujita H, Aratani S, Eguchi K, Komiya S, Maruyama I, Higashi N, Sato M, Senoo H, Ochi T, Yokoyama S, Amano T, Kim J, Gay S, Fukamizu A, Nishioka K, Tanaka K, Nakajima T.
    • Journal Title

      EMBO J. 26

      Pages: 113-22

    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Involvement of kinesin famiy member 2C/mitotic centromere-associated kinesin overexpression in mammary carcinogenesis.2007

    • Author(s)
      Arata Shimo, et. al.
    • Journal Title

      Cancer Sci. 99(1)

      Pages: 62-70

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Putative tumor suppressor EDD interacts with and up-regulates APC.2007

    • Author(s)
      Ryuichi Oshima, et. al.
    • Journal Title

      Genes Cells. 12(12)

      Pages: 1339-1345

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Modification of the Hepatic Mitochondrial Proteome in Response to Ischemic Preconditioning following Ischemia-Reperfusion Injury of the Rat Liver.2007

    • Author(s)
      Ryuichi Oshima, et. al.
    • Journal Title

      Eur Surg Res. 40(3)

      Pages: 247-255

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 治療効果予測マーカー-最近のトピック,basal-like乳癌に焦点を当てて-2007

    • Author(s)
      小池彩華, et. al.
    • Journal Title

      日本臨床 65(Sup.)

      Pages: 285-290

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] BRCA1 ubiqutinates RPB8 in response to DNA damage.2007

    • Author(s)
      Wenwen Wu
    • Journal Title

      Cancer Res. 67(3)

      Pages: 951-8

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Elevated expression of PRC1, involved in the growth of breast cancer cells.2007

    • Author(s)
      Arata Shimo, et al.
    • Journal Title

      Cancer Sci. 98(2)

      Pages: 174-81

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Cytoplasmic destruction of p53 by the endoplasmic reticulum-resident ubiquitin Iigase 'Synoviolin'.2007

    • Author(s)
      Satoshi Yamasaki, et al.
    • Journal Title

      EMBO J. 67(1)

      Pages: 113-22

    • Related Report
      2006 Annual Research Report
  • [Journal Article] 乳癌および卵巣癌抑制遺伝子BRCA12006

    • Author(s)
      太田 智彦
    • Journal Title

      PNE:蛋白核酸酵素 51

      Pages: 1395-1400

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Breast and ovarian cancer susceptibility product BRCA1.2006

    • Author(s)
      Ohta T.
    • Journal Title

      Protein Nucleic Acid and Enzyme(PNE) 51

      Pages: 1395-1400

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] 乳癌および卵巣癌抑制遺伝子BRCA12006

    • Author(s)
      太田智彦
    • Journal Title

      PNE : 蛋白核酸酵素 51(10 suppl)

      Pages: 1395-1400

    • Related Report
      2006 Annual Research Report
  • [Presentation] Cooperation of BRCA1 and ubiquitin in the DNA damage response2008

    • Author(s)
      太田 智彦
    • Organizer
      第23回名古屋癌治療国際シンポジウム
    • Place of Presentation
      名古屋
    • Year and Date
      2008-01-27
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Cooperation of BRCA1 and ubiquitin in the DNA damage response2008

    • Author(s)
      Ohta T.
    • Organizer
      The 23rd Nagoya international cancer treatment symposium
    • Place of Presentation
      Nagoya
    • Year and Date
      2008-01-27
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Cooperation of BRCAl and ubiquitin in the DNA damage response.2008

    • Author(s)
      Tomohiko Ohta
    • Organizer
      第23回名古屋癌治療国際シンポジウム
    • Place of Presentation
      名古屋
    • Year and Date
      2008-01-26
    • Related Report
      2007 Annual Research Report
  • [Presentation] 細胞周期およびDNA損傷反応におけるBRCA1ユビキチンリガーゼの分子機能2007

    • Author(s)
      太田 智彦, 他
    • Organizer
      第66回日本癌学会総会・シンポジウム
    • Place of Presentation
      横浜
    • Year and Date
      2007-10-03
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Molecular functions of BRCA1E3 ubiquitin ligase in cell cycle and DNA damage response2007

    • Author(s)
      Ohta T., Wu W., Fukuda M.
    • Organizer
      The 66th annual meeting of the Japanese cancer association
    • Place of Presentation
      Yokohama
    • Year and Date
      2007-10-03
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] 細胞周期およびDNA損傷におけるBRCA1ユビキチンリガーゼの分子機能2007

    • Author(s)
      太田 智彦, et. al.
    • Organizer
      第66回日本癌学会総会
    • Place of Presentation
      横浜
    • Year and Date
      2007-10-03
    • Related Report
      2007 Annual Research Report
  • [Presentation] 多様な細胞内径路を制御するBRCA1のユビキチンリガーゼ活性2006

    • Author(s)
      太田 智彦, 他
    • Organizer
      日本分子生物学会2006フォーラム・シンポジウム
    • Place of Presentation
      名古屋
    • Year and Date
      2006-12-07
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Ubiquitin ligase activity of BRCA1, a hub protein that regulates multiple cellular pathways2006

    • Author(s)
      Ohta T., Wu W., Fukuda M.
    • Organizer
      MBSJ forum 2006 of the molecular biology society of Japan
    • Place of Presentation
      Nagoya
    • Year and Date
      2006-12-07
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] ゲノム安定性維持におけるBRCA1酵素活性の役割2006

    • Author(s)
      太田 智彦
    • Organizer
      第49回日本放射線影響学会・シンポジウム
    • Place of Presentation
      札幌
    • Year and Date
      2006-09-08
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Roles of BRCA1's Enzyme Activity in the Maintenance of Genomic Stability2006

    • Author(s)
      Ohta T.
    • Organizer
      The 49th annual meeting of the Japan radiation research society
    • Place of Presentation
      Sapporo
    • Year and Date
      2006-09-08
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] BRCA1の酵素活性による乳癌および卵巣癌抑制2006

    • Author(s)
      太田 智彦
    • Organizer
      第43回日本臨床分子医学会学術集会・シンポジウム
    • Place of Presentation
      札幌
    • Year and Date
      2006-07-20
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Breast and ovarian tumor suppression by BRCA1's enzyme activity2006

    • Author(s)
      Ohta T.
    • Organizer
      The 43th congress of the Japanese society of molecular medicine
    • Place of Presentation
      Sapporo
    • Year and Date
      2006-07-20
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] 乳癌および卵巣癌抑制遺伝子産物BRCA1の酵素活性2006

    • Author(s)
      太田 智彦
    • Organizer
      第12回日本家族性腫瘍学会学術総会・シンポジウム
    • Place of Presentation
      吹田
    • Year and Date
      2006-06-16
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] The enzyme activity of breast and ovarian tumor suppresser BRCA12006

    • Author(s)
      Ohta T.
    • Organizer
      The 12th annual congress of the Japanese society for familial tumors
    • Place of Presentation
      Suita
    • Year and Date
      2006-06-16
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] 乳癌および卵巣癌抑制におけるBRCA1酵素活性の役割2006

    • Author(s)
      太田 智彦
    • Organizer
      第95回日本病理学会総会・シンポジウム
    • Place of Presentation
      新宿
    • Year and Date
      2006-04-30
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Roles of BRCA1's enzyme activity in breast and ovarian tumor Suppression2006

    • Author(s)
      Ohta T.
    • Organizer
      The 95th annual congress of the Japanese society of pathology
    • Place of Presentation
      Sinjuku
    • Year and Date
      2006-04-30
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Patent(Industrial Property Rights)] 癌の抑制方法2007

    • Inventor(s)
      太田 智彦
    • Industrial Property Rights Holder
      聖マリアンナ医科大学・太田 智彦
    • Acquisition Date
      2007-06-21
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Overseas
  • [Patent(Industrial Property Rights)] 癌の抑制方法2007

    • Inventor(s)
      太田智彦
    • Industrial Property Rights Holder
      聖マリアンナ医科大学・太田智彦
    • Acquisition Date
      2007-06-21
    • Related Report
      2007 Annual Research Report
    • Overseas

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Published: 2006-04-01   Modified: 2016-04-21  

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