Analysis for a new mechanism of neoplastic cell transformation through the centrosome control with MT1-MMP

2012 Fiscal Year Final Research Report

• Project/Area Number: 23650592
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Tumor biology
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: MIKI Yoshio 東京医科歯科大学, 難治疾患研究所, 教授 (10281594)
• Co-Investigator(Kenkyū-buntansha): NAKANISHI Akira 東京医科歯科大学, 難治疾患研究所, 特任准教授 (50321790)
• Project Period (FY): 2011 – 2012
• Keywords: ゲノム安定性 / 発がん / がん抑制遺伝子

Research Abstract

BRCA2 is a multifunctional tumor suppressor protein with critical roles in DNA repair, replication, centrosome amplification, and cytokinesis. We previously identified the complexes of BRCA2 and membrane type-1 matrix metalloproteinase (MT1-MMP). In addition, we found the cleaved BRCA2 by MT1-MMP in cancer cells. To examine the role of the cleaved BRCA2 fragments, we generated cleavage-site-directed antibodies, which specifically recognize each of the fragments of BRCA2 (N-BRCA2 or C-BRCA2). Immunofluorescence analysis revealed that C-BRCA2 localizes to discrete nuclear foci. We measured the fluorescence intensity of the wild-type BRCA2 and C-BRCA2 nuclear foci in HeLa cells exposed to 10 Gy of ionizing radiation at several time points after irradiation. Interestingly, the intensity of wild-type BRCA2 foci was stronger near thenuclear envelope compared with the central part, but the intensity of cleaved C-BRCA2 foci was distributed evenly in the nucleus after irradiation. We suggest that BRCA2 is a cleavage target of MT1-MMP and that cleaved C-BRCA2 may play an important role in HRand breast oncogenesis.

Research Products

• [Journal Article] Transforming mutations of RAC guanosine triphosphatases in human cancers (2013)
  • Author(s): Kawazu, M., Ueno, T., Kontani, K., Ogita, Y., Ando, M., Fukumura, K., Yamato, A., Soda, M., Takeuchi, K., Miki, Y., Yamaguchi, H., Yasuda, T., Naoe, T., Yamashita, Y., Katada, T., Choi, Y.L. and Mano, H
  • Journal Title: Proc Natl Acad Sci U S A Volume: 110 Pages: 3029-34
• [Journal Article] Whole-exome sequencing of human pancreatic cancers and characterization of genomic instability caused by MLH1 haploinsufficiency and complete deficiency (2012)
  • Author(s): Wang, L., Tsutsumi, S., Kawaguchi, T., Nagasaki, K., Tatsuno, K., Yamamoto, S., Sang, F., Sonoda, K., Sugawara, M., Saiura, A., Hirono, S., Yamaue, H., Miki, Y., Isomura, M., Totoki, Y., Nagae, G., Isagawa, T., Ueda, H., Murayama-Hosokawa, S., Shibata, T., Sakamoto, H., Kanai, Y., Kaneda, A., Noda, T. and Aburatani, H
  • Journal Title: Genome Res Volume: 22 Pages: 208-19
• [Journal Article] DYRK2 priming phosphorylation of c-Jun and c-Myc modulates cell cycle progression in human cancer cells (2012)
  • Author(s): Taira, N., Mimoto, R., Kurata, M., Yamaguchi, T., Kitagawa, M., Miki, Y. and Yoshida, K
  • Journal Title: J Clin Invest Volume: 122 Pages: 859-72
• [Journal Article] Programmed cell death 6, a novel p53-responsive gene, targets to the nucleus in the apoptotic response to DNA damage (2012)
  • Author(s): Suzuki, K., Dashzeveg, N., Lu, Z.G.,Taira, N., Miki, Y. and Yoshida, K
  • Journal Title: Cancer Sci Volume: 103 Pages: 1788-94
• [Journal Article] Clinical impact of intraoperative detection of carcinoembryonic antigen mRNA in pleural lavage specimens from nonsmall cell lung cancer patients (2012)
  • Author(s): Satoh, Y., Sugai, S., Uehara, H., Mun, M., Sakao, Y., Okumura, S., Nakagawa, K., Ishikawa, Y., Miki, Y. and Miyata, S
  • Journal Title: Thorac Cardiovasc Surg Volume: 60 Pages: 533-40
• [Journal Article] Reduction of NOTCH1 expression pertains to maturation abnormalities of keratinocytes in squamous neoplasms (2012)
  • Author(s): Sakamoto, K., Fujii, T., Kawachi, H., Miki, Y., Omura, K., Morita, K., Kayamori, K., Katsube, K. and Yamaguchi, A
  • Journal Title: Lab Invest Volume: 92 Pages: 688-702
• [Journal Article] Expression of basal cell keratin 15 and keratin 19 in oral squamous neoplasms represents diverse pathophysiologies (2012)
  • Author(s): Khanom, R., Sakamoto, K., Pal, S.K., Shimada, Y., Morita, K., Omura, K., Miki, Y. and Yamaguchi, A
  • Journal Title: Histol Histopathol Volume: 27 Pages: 949-59
• [Journal Article] High level of miR-21, miR-10b, and miR-31 expression in bilateral vs. unilateral breast carcinomas (2012)
  • Author(s): Iyevleva, A.G., Kuligina, E., Mitiushkina, N.V., Togo, A.V., Miki, Y. and Imyanitov, E.N
  • Journal Title: Breast Cancer Res Treat Volume: 131 Pages: 1049-59
• [Journal Article] A genome-wide association study identifies a genetic variant in the SIAH2 locus associated with hormonal receptor-positive breast cancer in Japanese (2012)
  • Author(s): Elgazzar, S., Zembutsu, H., Takahashi, A., Kubo, M., Aki, F., Hirata, K., Takatsuka, Y., Okazaki, M., Ohsumi, S., Yamakawa, T., Sasa, M., Katagiri, T., Miki, Y. and Nakamura, Y
  • Journal Title: J Hum Genet Volume: 57 Pages: 766-71
• [Journal Article] BRCA遺伝子と個別化治療.がん分子標的治療 (2012)
  • Author(s): 三木義男
  • Journal Title: がん種別の個別化治療の最前線 Volume: 10巻1号 Pages: 13-18
• [Journal Article] 遺伝性乳癌卵巣癌診療の新時代 (2012)
  • Author(s): 三木義男
  • Journal Title: BRCA1とBRCA2遺伝子産物の機能基礎から臨床.癌と化学療法 Volume: 39巻4号 Pages: 498-501
• [Journal Article] 乳癌の分子生物学と発癌機序発癌機序乳癌の発癌機序概論 (2012)
  • Author(s): 斉藤広子,三木義男
  • Journal Title: 乳癌(第2版)-基礎と臨床の最新研究動向- Volume: 70巻増刊7 Pages: 92-96
• [Presentation] Phosphorylation of BRCA2 by Akt is involved in BRCA2-14-3-3 gamma interaction related to centrosome dynamics (2012)
  • Author(s): Miyaguchi K,Miki Y, Nakanishi A
  • Organizer: 15th International Congress on Hormonal Steroids and Hormones& Cancer
  • Place of Presentation: Kanazawa
  • Year and Date: 20121115-17
• [Presentation] Hereditary breast/ovarian cancer -New development of the molecular diagnosis and treatment-遺伝性乳がん・卵巣がん症候群-分子診断・治療の新たな展開 (2012)
  • Author(s): 三木義男,中西啓
  • Organizer: 第71回日本癌学会学術総会シンポジウム
  • Place of Presentation: 札幌市
  • Year and Date: 20120919-21
• [Presentation] Phosphorylation of BRCA2 by Akt is involved in BRCA2-14-3-3 gamma interaction related to centrosome dynamics 中心体制御に関わるBRCA2‐14-3-3γ複合体形成にはAktによるBRCA2のリン酸化が関与する (2012)
  • Author(s): 宮口健,郭甜甜,三木義男,中西啓
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌市
  • Year and Date: 20120919-21
• [Presentation] Proteasome activity affects cancerous centrosome hypertrophy プロテアソームの活性は癌細胞における中心体の肥大化に影響する (2012)
  • Author(s): 木村仁美,中西啓,三木義男
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌市
  • Year and Date: 20120919-21
• [Presentation] BRCA2 contributes success of cytokinesis through regulation ofnon-muscle myosin IIC ATPase activity乳癌原因遺伝子産物BRCA2はII型ミオシンIICのATPase活性の制御を通して細胞質分裂に働く (2012)
  • Author(s): 高岡美帆,斉藤広子,中西啓,三木義男
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌市
  • Year and Date: 20120919-21
• [Presentation] The correlation of decorin and periostin indicated by the proteomics of phyllodes葉状腫瘍のプロテオーム解析から導いたdecorinとperiostinの関連性 (2012)
  • Author(s): 石場俊之,中西啓,高木洋子,笠原舞,杉本斉,永原誠,中川剛士,佐藤隆宣,杉原健一,三木義男
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌市
  • Year and Date: 20120919-21
• [Presentation] BRCA2の新規機能と合成致死理論に基づく新規乳癌治療法開発の可能性 (2012)
  • Author(s): 三木義男,中西啓
  • Organizer: 第20回日本乳癌学会学術総会
  • Place of Presentation: 熊本市
  • Year and Date: 20120000
• [Presentation] 切断型BRCA2の形成機序および機能解析
  • Author(s): 中西啓,Nadila Wali,斉藤広子,大(1)研究代表者海,三木義男
  • Organizer: 日本人類遺伝学会第57回大会
  • Place of Presentation: 新宿区
  • Year and Date: 00001025-27
• [Remarks]
  • URL: http://www.tmd.ac.jp/mri/section/genomics/mg/index.html