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

• 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
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2012: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2011: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: ゲノム安定性 / 発がん / がん抑制遺伝子 / 乳がん / MT1-MMP / BRCA2 / 中心体

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] (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 YL, Mano H,
  • Journal Title: Proc Natl Acad Sci U S A Volume: 110 Issue: 8 Pages: 3029-3034
  • DOI: 10.1073/pnas.1216141110
  • Peer Reviewed
• [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
  • NAID: 10031145883
• [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
• [Journal Article] A genome-wide association study identifies a genetic variant in the SIAH2 locus associated with (2012)
  • Author(s): Elgazzar S,
  • Journal Title: J Hum Genet Volume: 57 Issue: 12 Pages: 766-71
  • DOI: 10.1038/jhg.2012.108
  • Peer Reviewed
• [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): Kazuho Suzuki
  • Journal Title: Cancer Sci. Volume: 103 Issue: 10 Pages: 1788-1794
  • DOI: 10.1111/j.1349-7006.2012.02362.x
  • Peer Reviewed
• [Journal Article] Expression of basal cell keratin 15 and keratin 19 in oral squamous neoplasms represents diverse pathophysiologies. (2012)
  • Author(s): Khanom R,
  • Journal Title: Histol Histopathol. Volume: 27 Pages: 949-59
  • Peer Reviewed
• [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 KI, Kayamori K, Katsube KI, Yamaguchi A
  • Journal Title: Laboratory investigation Volume: (Epub ahead of print) Issue: 5 Pages: 688-702
  • DOI: 10.1038/labinvest.2012.9
  • Peer Reviewed
• [Journal Article] DYRK2 priming phosphorylation of c-Jun and c-Myc modulates cell cycle progression in human cancer cells (2012)
  • Author(s): Taira N., et al
  • Journal Title: The Journal of Clinical Investigation Volume: 122 Issue: 3 Pages: 859-872
  • DOI: 10.1172/jci60818
  • Peer Reviewed
• [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, Miyata S.
  • Journal Title: Thorac Cardiovasc Surg Volume: 60 Issue: 8 Pages: 533
  • DOI: 10.1055/s-0031-1298066
  • Peer Reviewed
• [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, SangF, 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,Aburatani H
  • Journal Title: Genome Research Volume: 22(2) Issue: 2 Pages: 208-19
  • DOI: 10.1101/gr.123109.111
  • Peer Reviewed
• [Journal Article] High level of miR-21, miR-10b, and miR-31 expression in bilateral vs. unilateral breast carcinomas. (2012)
  • Author(s): Iyevleva AG,
  • Journal Title: Breast Cancer Res Treat. Volume: 13 Issue: 3 Pages: 1049-59
  • DOI: 10.1007/s10549-011-1845-z
  • Peer Reviewed
• [Journal Article] ［遺伝性乳癌卵巣癌診療の新時代］BRCA1とBRCA2遺伝子産物の機能 基礎から臨床 (2012)
  • Author(s): 三木 義男
  • Journal Title: 癌と化学療法 Volume: 39 Pages: 498-501
• [Journal Article] ［がん種別の個別化治療の最前線］BRCA遺伝子と個別化治療 (2012)
  • Author(s): 三木 義男
  • Journal Title: がん分子標的治療 Volume: 10 Pages: 13-18
• [Journal Article] ［乳癌(第2版)-基礎と臨床の最新研究動向-］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(分子機構、多段階発癌機序を含めて) (2012)
  • Author(s): 斉藤 広子
  • Journal Title: 日本臨床 Volume: 70巻増刊7 Pages: 92-96
• [Journal Article] ［個別化薬物療法-始まっている臨床応用］分子標的薬の個別化医療 (2012)
  • Author(s): 須貝 幸子
  • Journal Title: 薬事 Volume: 54 Pages: 919-923
• [Journal Article] High level of miR-21, miR-10b, and miR-31 expression in bilateral vs. unilateral breast carcinomas. (2012)
  • Author(s): Iyevleva AG, Kuligina ESh, Mitiushkina NV, Togo AV, Miki Y, Imyanitov EN.
  • Journal Title: Breast Cancer Res Treat. Volume: 131 Pages: 1049-1059
  • Peer Reviewed
• [Journal Article] BRCA2 and nucleophosmin coregulate centrosome amplification and form a complex with the Rho effector kinase ROCK2. (2011)
  • Author(s): Wang HF, Takenaka K, Nakanishi A, Miki Y.
  • Journal Title: Cancer Res. Volume: 71 Pages: 68-77
  • Peer Reviewed
• [Journal Article] Prospective randomized phase II study determines the clinical usefulness of genetic biomarkers for sensitivity to primary chemotherapy with paclitaxel in breast cancer. (2011)
  • Author(s): Ito Y, Nagasaki K, Miki Y, Iwase T, Akiyama F, Matsuura M, Horii R, Makita M, Tokudome N, Ushijima M, Yoshimoto M, Takahashi S, Noda T, Hatake K.
  • Journal Title: Cancer Sci. Volume: 102 Pages: 130-6
  • NAID: 10029288759
  • Peer Reviewed
• [Journal Article] PKCδ regulates Mdm2 independently of p53 in the apoptotic response to DNA damage. (2011)
  • Author(s): Hew HC, Liu H, Miki Y, Yoshida K.
  • Journal Title: Mol Carcinog. Volume: 50 Pages: 719-31
  • Peer Reviewed
• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [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
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌市
  • Invited
• [Presentation] 遺伝性乳がん卵巣がんの現状 問題点と展望 遺伝性乳がん原因遺伝子BRCA2の新規機能と新たな治療法開発の試み． (2012)
  • Author(s): 三木 義男
  • Organizer: 第18回日本家族性腫瘍学会学術集会
  • Place of Presentation: 大阪市
  • Invited
• [Presentation] 乳癌新規予後予測因子Stathmin1の検討 (2012)
  • Author(s): 三木 義男
  • Organizer: 第20回日本乳癌学会学術総会
  • Place of Presentation: 熊本市
• [Presentation] Dysregulation of c-Jun/c-Myc expression by depletion of DYRK2 triggers tumorigenesis DYRK2の発現欠失によるc-Jun/c-Mycの制御異常は細胞の腫瘍化を引き起こす (2012)
  • Author(s): 三木 義男
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌市
• [Presentation] Analysis of a centrosome localization signal （CLS） in BRCA2 BRCA2由来中心体局在化シグナル（CLS）の機能解析 (2012)
  • Author(s): 三木 義男
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌市
• [Presentation] BRCA2 contributes success of cytokinesis through regulation of non-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): 三木 義男
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌市
• [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): 三木 義男
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌市
• [Presentation] BRCA1/2研究の現状と展望 (2011)
  • Author(s): 三木義男
  • Organizer: 第17回日本家族性腫瘍学会学術集会(招待講演)
  • Place of Presentation: 京都市
• [Presentation] 遺伝性乳がん・卵巣がん症候群の分子遺伝 (2011)
  • Author(s): 三木義男
  • Organizer: 第47回北九州乳腺カンファレンス(招待講演)
  • Place of Presentation: 北九州市
• [Presentation] BRCA1/2遺伝子の分子生物学－遺伝子の発見から今、そして今後の展望－ (2011)
  • Author(s): 三木義男
  • Organizer: 第14回家族性腫瘍セミナー(招待講演)
  • Place of Presentation: 東大阪市
• [Presentation] New insights into the cellular function of BRCA2. (2011)
  • Author(s): Miki Y, Takenaka K, Nakanishi A.
  • Organizer: 70th Annual Meeting of the Japanese Cancer Association(招待講演)
  • Place of Presentation: Nagoya, Japan,
• [Presentation] 網羅的遺伝子発現情報のがん個別化治療への展開 (2011)
  • Author(s): 三木義男
  • Organizer: 第35回日本頭頸部癌学会
  • Place of Presentation: 名古屋市
• [Presentation] BRCA1/2遺伝子検査の先進医療への取組み (2011)
  • Author(s): 三木義男
  • Organizer: 第19回日本乳癌学会学術総会
  • Place of Presentation: 仙台市
• [Presentation] 遺伝性乳癌・卵巣癌症候群－基礎から臨床－ (2011)
  • Author(s): 三木義男、 斉藤広子、 中西啓
  • Organizer: 日本人類遺伝学会第56回大会・第11回東アジア人類遺伝学会
  • Place of Presentation: 千葉市
• [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
• [Remarks]
  • URL: http://www.tmd.ac.jp/mri/section/genomics/mg/index.html
• [Remarks] 東京医科歯科大学 難治疾患研究所 分子遺伝分野
  • URL: http://www.tmd.ac.jp/mri/mgen/index_j.html