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IDENTIFICATION AND FUNCTIONAL ANALYSES OF THE GENES RELATED TO HEREDITARY BREAST CANCER

Research Project

Project/Area Number 12213141
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionTOKYO MEDICAL AND DENTAL UNIVERSITY (2002-2004)
Japanese Foundation For Cancer Research (2000-2001)

Principal Investigator

YOSHO Miki  TOKYO MEDICALAND DENTAL UNIVERSITY MEDICALRESEARCH INSTITUTE, PROFESSOR, 難治疾患研究所, 教授 (10281594)

Project Period (FY) 2000 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥77,300,000 (Direct Cost: ¥77,300,000)
Fiscal Year 2004: ¥15,000,000 (Direct Cost: ¥15,000,000)
Fiscal Year 2003: ¥15,600,000 (Direct Cost: ¥15,600,000)
Fiscal Year 2002: ¥16,000,000 (Direct Cost: ¥16,000,000)
Fiscal Year 2001: ¥15,700,000 (Direct Cost: ¥15,700,000)
Fiscal Year 2000: ¥15,000,000 (Direct Cost: ¥15,000,000)
KeywordsHEREDITARY BREAST CANCER / BRCA1 / BRCA2 / DNA DAMAGE REPAIR / CYTOKINESIS / CYTOSKELETON / APOPTOSIS / 遺伝性乳癌 / Two hybrid法 / 遺伝子発現プロファイル / Two-hybrid法 / RNAi法 / RFX4 / NTKL / DNA損傷 / 臨床検査 / mel-18 / 核移行シグナル / BRCA2関連タンパク
Research Abstract

BRCA1 and BRCA2 were identified as a responsible gene of hereditary breast cancers, and presymptomatic diagnosis demonstrates big power clinically. It is thought that BRCA1 and BRCA2 are caretaker type antioncogenes which work to genome stabilization. Then, we focused on BRCA2, and tried to identify the molecules combined with the BRCA2 protein, and to elucidate the physiological function of BRCA2 based on the meaning of the signal transduction. It is thought that this research greatly contributes to the understanding of the meaning of the signal transduction borne by the target molecule, i. e., the mechanism of breast carcinogenesis.
We showed that two or more nuclear localization signals exist in C terminal of BRCA2, and nuclear export signals are among these. We presumed they functioned integrative and controlled subcellular localization of BRCA2. Moreover, it was shown clearly that Rad51 combines with BRCA2, and BRCA is participating in the double strand break repair of DNA. On the other hand, BRCA2 protein is combined with cytoskeletons, such as myosin, plectin, actinin, and γ-tubulin. BRCA2 is distributed in the nucleus and also around the nucleus toward the centrosome in the cell of G1-S, and colocalizing with γ-tubulin gradually in G2-M. It exists as phosphorylated protein around the chromosomes at M stage. From these results, it was supposed that subcellular localization of BRCA2 differed with each stage of cell cycle, and BRCA2 protein was carrying out the important work in cytokinesis. Furthermore, it identified that TRAF1 and Tax binding protein interacted with BRCA2, and a possibility that BRCA2 would control the apoptosis through NF-kappa B was shown. Taken together, BRCA2 is considered to have functions of DNA damage repair, cytokinesis regulation, and apoptosis control, and to function on homeostasis comprehensively.

Report

(6 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • 2002 Annual Research Report
  • 2001 Annual Research Report
  • 2000 Annual Research Report
  • Research Products

    (36 results)

All 2005 2004 Other

All Journal Article (20 results) Publications (16 results)

  • [Journal Article] JNK phosphorylation of 14-3-3 regulates nuclear targeting of c-Ab1 in the apoptotic response to DNA damage.2005

    • Author(s)
      Yoshida, K.et al.
    • Journal Title

      Nat Cell Biol. 7

      Pages: 278-285

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] JNK phosphorylation of 14-3-3 regulates nuclear targeting of c-Abl In the apoptotic response to DNA damage.2005

    • Author(s)
      Yoshida, K., Yamaguchi, T., Natsume, T., Kufe, D., Miki Y.
    • Journal Title

      Nat Cell Biol. 7

      Pages: 278-285

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] JNK phosphorylation of 14-3-3 regulates nuclear targeting of c-Ablin the apoptotic response to DNA damage.2005

    • Author(s)
      Yoshida, K. et al.
    • Journal Title

      Nature Cell Biology 7

      Pages: 278-285

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Role of BRCA1 and BRCA2 as regulators of DNA repair, transcription, and cell cycle in response to DNA damage.2004

    • Author(s)
      Yoshida, K.et al.
    • Journal Title

      Cancer Sci. 95

      Pages: 866-871

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Genome-wide gene-expression profiles of breast-cancer cells purified with laser microbeam microdissection : identification of genes associated with progression and metastasis.2004

    • Author(s)
      Nishidate, T.et al.
    • Journal Title

      Int J Oncol. 25

      Pages: 797-819

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Familial breast and ovarian cancers.2004

    • Author(s)
      Arai, M.et al.
    • Journal Title

      Int J Clin Oncol. 4

      Pages: 270-282

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Relatively common mutations of the Bloom syndrome gene in the Japanese population.2004

    • Author(s)
      Kaneko, H.et al.
    • Journal Title

      Int.J.Mol.Med. 14

      Pages: 439-442

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Gene expression patterns as marker for 5-year postoperative prognos is of primary breast cancers.2004

    • Author(s)
      Onda, M.et al.
    • Journal Title

      J.Cancer Res.Clin.Oncol 130

      Pages: 537-545

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Role of BRCA1 and BRCA2 as regulators of DNA repair, transcription, and cell cycle in response to DNA damage.2004

    • Author(s)
      Yoshida, K., Miki. Y.
    • Journal Title

      Cancer Sci. 95

      Pages: 866-871

    • NAID

      10014197645

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Genome-wide gene-expression profiles of breast-cancer cells purified with laser microbeam microdissection : identification of genes associated with progression and metastasis.2004

    • Author(s)
      Nishidate, T., Katagiri, T., Lin, M.L., Mano, Y., Miki.Y.Kasumi, F., Yoshimoto, M., Tsunoda, T., Hirata, K., Nakamura, Y.
    • Journal Title

      Int J Oncol. 25

      Pages: 797-819

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Familial breast and ovarian cancers.2004

    • Author(s)
      Arai, M., Utsunomiya, J., Miki.Y.
    • Journal Title

      Int J Clin Oncol. 4

      Pages: 270-282

    • NAID

      10013569457

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Relatively common mutations of the Bloom syndrome gene in the Japanese population.2004

    • Author(s)
      Kaneko, H., Isogai, K., Fukao, T., Matsui, E., Kasahara, K., Yachie, A., Seki, H., Koizumi, S., Arai, M., Utsunomiya, J., Miki.Y., Kondo, N.
    • Journal Title

      Int.J.Mol.Med. 14

      Pages: 439-442

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Gene expression patterns as marker for 5-year postoperative prognosis of primary breast cancers.2004

    • Author(s)
      Onda, M., Emi, M., Nagai, H., Nagahata, T., Tsumagari, K., Fujimoto, T., Akiyama, F., Sakamoto, G., Makita, M., Kasumi, F., Miki Y Tanaka, T., Tsunoda, T., Nakamura, Y.
    • Journal Title

      J.Cancer Res.Clin.Oncol. 130

      Pages: 537-545

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Expression profiling to predict postoperative prognosis for estrogen receptor-negative breast cancers by analysis of 25,344 genes on a cDNA microarray.2004

    • Author(s)
      Nagahata, T., Onda, M., Emi, M., Nagai, H., Tsumagari, K., Fujimoto, T., Hirano, A., Sato, T., Nishikawa, K., Akiyama, F., Sakamoto, G., Kasumi, F., Miki.Y..Tanaka, T., Tsunoda, T.
    • Journal Title

      Cancer Sci. 95

      Pages: 218-225

    • NAID

      10013721729

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Genotyping of single nucleotide polymorphism using model-based clustering.2004

    • Author(s)
      Fujisawa, H., Eguchi, S., Ushijima, M., Miyata, S., Miki.Y., Muto, T., Matsuura, M.
    • Journal Title

      Bioinformatics. 20

      Pages: 718-726

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Genome-wide gene-expression profiles of breast-cancer cells purified with laser microbeam microdissection : identification of genes associated.2004

    • Author(s)
      Nishidate, T. et al.
    • Journal Title

      Int J Oncol. 25

      Pages: 797-819

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Relatively common mutations of the Bloom syndrome gene in the Japanese population.2004

    • Author(s)
      Kaneko, H. et al.
    • Journal Title

      Int J Mol Med 14

      Pages: 439-442

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Expression profiling to predict postoperative prognosis for estrogen receptor-negative breast cancers by analysis of 25,344 genes on a cDNA microarray.2004

    • Author(s)
      Nagahata, T. et al.
    • Journal Title

      Cancer Sci. 95

      Pages: 218-225

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Genotyping of single nucleotide polymorphism using model-based clustering.2004

    • Author(s)
      Fujisawa, H. et al.
    • Journal Title

      Bioinformatics 20

      Pages: 718-726

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Role of BRCA1 and BRCA2 as regulators of DNA repair, transcription, and cell cycle in response to DNA damage.2004

    • Author(s)
      Yoshida, K., Miki, Y.
    • Journal Title

      Cancer Sci. 95

      Pages: 866-871

    • NAID

      10014197645

    • Related Report
      2004 Annual Research Report
  • [Publications] Yoshida K, Wang HG, Miki Y, Kufe D.: "Protein kinase Cdelta is responsible for constitutive and DNA damage-induced phosphorylation of Rad9"EMBO J.. 22. 1431-1441 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Fujisawa H, Eguchi S, Ushijima M, Miyata S, Miki Y, et al.: "Genotyping of single nucleotide polymorphism using model-based clustering."Bioinformatics.. (Epub ahead of print.). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Morotomi-Yano, K., et al.: "Human regulatory factor X4 (RFX4) is a testis-specific dimeric DNA-binding protein that cooperates with other human RFX members"J. Biol. Chem.. 277. 836-842 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kato, M., et al.: "Identification and characterization of the human protein kinase-like gene NTKL : mitosis-specific centrosomal localization of an alternatively"Genomics. 79. 760-767 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Imai, Y., et al.: "C421A polymorphism in the human breast cancer resistance protein gene is associated with low expression of Q141K protein and low-level drug"Mol. Cancer Therapeutics. 1. 611-616 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kokudo, N., et al.: "Genetic and histological assessment of surgical margins in resected liver metastases from colorectal carcinoma"Arch Surg.. 137. 833-840 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yoshida, K., et al.: "Activation of SAPK/JNK Signaling by Protein Kinase C in Response to DNA Damage"J. Biol. Chem.. 277. 48372-48378 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yoshida, K., et al.: "Protein kinase Cδ is responsible for constitutive and DNA damage-induced phosphorylation of Rad9"EMBO J.. (In press).

    • Related Report
      2002 Annual Research Report
  • [Publications] Haga, S., et al.: "Association of allelic losses at 3p25.1, 13q12, or 17p13.3 with poor prognosis in breast cancers with lymph node metasasis"Jpn. J. Cancer Res.. 92. 1199-1206 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Matsuo, F., et al.: "Mutation analysis of the mel-18 gene that shows decreased expression in breast cancer cell lines"Breast Cancer. 9. 33-38 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Morotomi-Yano, K., et al.: "Human regulatory factor X4(RFX4) is a testis-specific dimeric DNA-binding protein that cooperates with other human RFX members"Oncogene.. 277. 836-842 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Takata, M., et al.: "Conserved domains in the chicken homologue of BRCA2.Oncogene"Journal of Biological Chemistry. 21. 1130-1134 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kato, M., et al.: "Identification and characterization of the human protein kinase-like gene NTKL : mitosis-specific centrosomal localization of an altematively spliced isoform"Genomics. (in press).

    • Related Report
      2001 Annual Research Report
  • [Publications] Kato,M., et al.: "Identification of Rad51 alteration in patients with bilateral breast cancer."J Hum.Genet.. 45. 133-137 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Yano,K., et al.: "Nuclear Localization signals of the BRCA2 protein."Biochem Biophys Res Commun.. 270. 171-175 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Futamura,M., et al.: "Potential role of BRCA2 in a mitotic checkpoint after phosphorylation by hBUBR1."Cancer Res.. 60. 1531-1535 (2000)

    • Related Report
      2000 Annual Research Report

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Published: 2000-04-01   Modified: 2018-03-28  

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