Regulatory mechanisms of breast cancer cells in the apoptotic response to DNA damage

• Project/Area Number: 19390083
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: MIKI Yoshio Tokyo Medical and Dental University, 難治疾患研究所, 教授 (10281594)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥17,940,000 (Direct Cost: ¥13,800,000、Indirect Cost: ¥4,140,000); Fiscal Year 2008: ¥8,580,000 (Direct Cost: ¥6,600,000、Indirect Cost: ¥1,980,000); Fiscal Year 2007: ¥9,360,000 (Direct Cost: ¥7,200,000、Indirect Cost: ¥2,160,000)
• Keywords: 乳腺発がん / DNA損傷修復 / 細胞死誘導 / c-Abl / 14-3-3 / TAF1 / c-Ab1 / shRNAライブラリー / 乳癌 / 細胞死 / トポイソメラーゼIIα / 酸化ストレス / ユビキチン化

Research Abstract

DNA損傷に関わる機構の破綻は、癌をはじめとする広範な疾患の原因となる。我々は、乳癌においてDNA損傷に誘導される細胞死(アポトーシス)の制御機構の解明を目指し、このシグナル伝達を担ういくつかのキナーゼに焦点を絞り機能解析を進めた。その結果、(1) トポイソメラーゼIIα、RbとBRCA1、(2) c-Ablと14-3-3、(3) TAF1などの分子に関わる、乳癌における新たな細胞死誘導機構およびその破綻のメカニズムを明らかにした。

Research Products

• [Journal Article] A CRM1-mediated nuclear export signal governs cytoplasmic localization of BRCA2 and is essential for centrosomal localization of BRCA2 (2008)
  • Author(s): Han, X., Saito, H., Miki, Y.,*and Nakanishi, A
  • Journal Title: Oncogene 27 Pages: 2969-77
  • Peer Reviewed
• [Journal Article] Molecular epidemiological and mutational analysis of DNA mismatch repair(MMR)genes in endometrial cancer patients with HNPCC-associated familial predisposition to cancer (2008)
  • Author(s): Hirai, Y., Banno, K., Suzuki, M., Ichikawa, Y., Udagawa, Y., Sugano, K., and Miki, Y
  • Journal Title: Cancer Sci 99 Pages: 1715-9
  • Peer Reviewed
• [Journal Article] IL12RB2 and ABCA1 genes are associated with susceptibility to radiation dermatitis (2008)
  • Author(s): Isomura, M., Oya, N., Tachiiri, S., Kaneyasu, Y., Nishimura, Y., Akimoto, T., Hareyama, M., Sugita, T., Mitsuhashi, N., Yamashita, T., Aoki, M., Sai, H., Hirokawa, Y., Sakata, K., Karasawa, K., Tomida, A., Tsuruo, T., Miki, Y.,* Noda, T., and Hiraoka, M
  • Journal Title: Clin Cancer Res 14 Pages: 6683-9
  • Peer Reviewed
• [Journal Article] A Japanese patient with Li-Fraumeni syndrome who had nine primary malignancies associated with a germline mutation of the p53 tumor-suppressor gene (2008)
  • Author(s): Izawa, N., Matsumoto, S., Manabe, J., Tanizawa, T., Hoshi, M., Shigemitsu, T., Machinami, R., Kanda, H., Takeuchi, K., Miki, Y., Arai, M., Shirahama, S., and Kawaguchi, N
  • Journal Title: Int J Clin Oncol 13 Pages: 78-82
  • NAID: 10024141710
  • Peer Reviewed
• [Journal Article] A functional genome-wide RNAi screen identifies TAF1 as a regulator for apoptosis in response to genotoxic stress (2008)
  • Author(s): Kimura, J., Nguyen, S. T., Liu, H., Taira, N., Miki, Y.,*and Yoshida, K
  • Journal Title: Nucleic Acids Res 36 Pages: 5250-9
  • Peer Reviewed
• [Journal Article] Molecular prediction of the therapeutic response to neoadjuvant chemotherapy in breast cancer (2008)
  • Author(s): Nagasaki, K., and Miki, Y
  • Journal Title: Breast Cancer 15 Pages: 117-20
  • NAID: 10025371689
  • Peer Reviewed
• [Journal Article] TTK/Mps1 controls nuclear targeting of c-Abl by 14-3-3-coupled phosphorylation in response to oxidative stress (2008)
  • Author(s): Nihira, K., Taira, N., Miki, Y.,*and Yoshida, K
  • Journal Title: Oncogene 27 Pages: 7285-95
  • Peer Reviewed
• [Journal Article] Identification of the molecular mechanisms for dedifferentiation at the invasion front of colorectal cancer by a gene expression analysis (2008)
  • Author(s): Oku, Y., Shimoji, T., Takifuji, K., Hotta, T., Yokoyama, S., Matsuda, K., Higashiguchi, T., Tominaga, T., Nasu, T., Tamura, K., Matsuura, M., Miyata, S., Kato, Y., Yamaue, H., and Miki, Y
  • Journal Title: Clin Cancer Res 14 Pages: 7215-22
  • Peer Reviewed
• [Journal Article] BRCA1-mediated ubiquitination inhibits topoisomerase II alpha activity in response to oxidative stress (2008)
  • Author(s): Shinagawa, H., Miki, Y.,*and Yoshida, K
  • Journal Title: Antioxid Redox Signal 10 Pages: 939-49
  • Peer Reviewed
• [Journal Article] Recurrence pattern and rapid intraoperative detection of carcinoembryonic antigen(CEA)mRNA in pleural lavage in patients with non-small cell lung cancer(NSCLC) (2008)
  • Author(s): Sugai, S., Satoh, Y., Komatsu, M., Okumura, S., Nakagawa, K., Ishikawa, Y., and Miki, Y
  • Journal Title: Rinsho Byori 56 Pages: 851-7
  • NAID: 10024960497
  • Peer Reviewed
• [Journal Article] Cross-sectional analysis of germline BRCA1 and BRCA2 mutations in Japanese patients suspected to have hereditary breast/ovarian cancer (2008)
  • Author(s): Sugano, K., Nakamura, S., Ando, J., Takayama, S., Kamata, H., Sekiguchi, I., Ubukata, M., Kodama, T., Arai, M., Kasumi, F., Hirai, Y., Ikeda, T., Jinno, H., Kitajima, M., Aoki, D., Hirasawa, A., Takeda, Y., Yazaki, K., Fukutomi, T., Kinoshita, T., Tsunematsu, R., Yoshida, T., Izumi, M., Umezawa, S., Yagata, H., Komatsu, H., Arimori, N., Matoba, N., Gondo, N., Yokoyama, S., and Miki, Y
  • Journal Title: Cancer Sci 99 Pages: 1967-76
  • NAID: 10024011931
  • Peer Reviewed
• [Journal Article] Aurora kinase B is a predictive factor for the aggressive recurrence of hepatocellular carcinoma after curative hepatectomy (2008)
  • Author(s): Tanaka, S., Arii, S., Yasen, M., Mogushi, K., Su, N. T., Zhao, C., Imoto, I., Eishi, Y., Inazawa, J., Miki, Y., and Tanaka, H
  • Journal Title: Br J Surg 95 Pages: 611-9
  • Peer Reviewed
• [Journal Article] Novel BRCA2-interacting protein BJ-HCC-20A inhibits the induction of apoptosis in response to DNA damage (2008)
  • Author(s): Tomiyoshi, G., Nakanishi, A., Takenaka, K., Yoshida, K., and Miki, Y
  • Journal Title: Cancer Sci 99 Pages: 747-54
  • NAID: 10024004963
  • Peer Reviewed
• [Journal Article] A functional genome-wide RNAi screen identifies TAF1 as a regulator for apoptosis in response to genotoxic stress. (2008)
  • Author(s): Kimura, J., et al.
  • Journal Title: Nucleic Acids Res 36 Pages: 5250-9
  • Peer Reviewed
• [Journal Article] TTK/Mps1 controls nuclear targeting of c-Abl by 14-3-3-coupledphosphorylation in response to oxidative stress. (2008)
  • Author(s): Nihira, K., et al.
  • Journal Title: Oncogene 27 Pages: 7285-95
  • Peer Reviewed
• [Journal Article] BRCA1-mediated ubiquitination inhibits topoisomerase II alpha activity in response to oxidative stress. (2008)
  • Author(s): Shinagawa, H., et al.
  • Journal Title: Antioxid Redox Signal 10 Pages: 939-49
  • Peer Reviewed
• [Journal Article] Identification of novel deletion polymorphisms in breast cancer. (2008)
  • Author(s): Komatsu, A., et al.
  • Journal Title: Int J Oncol 33 Pages: 261-70
  • Peer Reviewed
• [Journal Article] Novel BRCA2-interacting protein BJ-HCC-20A inhibits the induction of apoptosis in response to DNA damage. (2008)
  • Author(s): Tomiyoshi, G., et al.
  • Journal Title: Cancer Sci 99 Pages: 747-54
  • Peer Reviewed
• [Journal Article] Cross-sectional analysis of germline BRCA1 and BRCA2 mutationsin Japanese patients suspected to have hereditary breast/ovarian cancer. (2008)
  • Author(s): Sugano, K., et al.
  • Journal Title: Cancer Sci 99 Pages: 1967-76
  • Peer Reviewed
• [Journal Article] BRCA1-mediated ubiquitination inhibits topoisomerase II alpha activity in response to oxidative stress. (2008)
  • Author(s): Shinagawa H, et. al.
  • Journal Title: Antioxid Redox Signal. 10 Pages: 939-950
  • Peer Reviewed
• [Journal Article] Reduced Levels of ATF-2 Predispose Mice to Mammary Tumors (2007)
  • Author(s): Maekawa T, Shinagawa T, Sano Y, Sakuma T, Nomura S, Nagasaki K, Miki Y, Saito-Ohara F, Inazawa J, Kohno T, Yokota J, Ishii S
  • Journal Title: Mol Cell Biol 27 Pages: 1730-44
  • Peer Reviewed
• [Journal Article] Frequent reduced expression of alpha-1B-adrenergic receptor caused by aberrant promoter methylation in gastric cancers (2007)
  • Author(s): Noda H, Miyaji Y, Nakanishi A, Konishi F, Miki Y
  • Journal Title: Br J Cancer 96 Pages: 383-90
  • Peer Reviewed
• [Journal Article] Functional pathway characterized by gene expression analysis of supraclavicular lymph node metastasis-positive breast cancer (2007)
  • Author(s): Oishi Y, Nagasaki K, Miyata S, Matsuura M, Nishimura S, Akiyama F, Iwai T, Miki Y
  • Journal Title: J Hum Genet 52 Pages: 271-9
  • NAID: 10018554326
  • Peer Reviewed
• [Journal Article] Interference with BRCA2, which localizes to the centrosome during S and early M phase, leads to abnormal nuclear division (2007)
  • Author(s): Nakanishi A, Han X, Saito H, Taguchi K, Ohta Y, Imajoh-Ohmi S, Miki Y
  • Journal Title: Biochem Biophys Res Commun 355 Pages: 34-40
  • Peer Reviewed
• [Journal Article] Identification of a predictive gene expression signature of cervical lymph node metastasis in oral squamous cell carcinoma (2007)
  • Author(s): Nguyen ST, Hasegawa S, Tsuda H, Tomioka H, Ushijima M, Noda M, Omura K, Miki Y
  • Journal Title: Cancer Sci 98 Pages: 740-6
  • Peer Reviewed
• [Journal Article] DYRK2 is targeted to the nucleus and controls p53 via Ser46 phosphorylation in the apoptotic response to DNA damage (2007)
  • Author(s): Taira N, Nihira K, Yamaguchi T, Miki Y, Yoshida K
  • Journal Title: Mol Cell 25 Pages: 725-38
  • Peer Reviewed
• [Journal Article] Protein kinase C delta activates IkappaB-kinase alpha to induce the p53 tumor suppressor in response to oxidative stress (2007)
  • Author(s): Yamaguchi T, Miki Y, * Yoshida K
  • Journal Title: Cell Signal 19 Pages: 2088-97
  • Peer Reviewed
• [Journal Article] Identifying haplotype block structure using an ancestor-derived model (2007)
  • Author(s): Fujisawa H, Isomura M, Eguchi S, Ushijima M, Miyata S, Miki Y, Matsuura M
  • Journal Title: J Hum Gene 52 Pages: 738-46
  • NAID: 10019812610
  • Peer Reviewed
• [Journal Article] The Deubiquitinating Enzyme USP11 Controls an I{kappa}B Kinase{alpha}(IKK {alpha})-p53 Signaling Pathway in Response to Tumor Necrosis Factor{alpha}(TNF {alpha}) (2007)
  • Author(s): Yamaguchi T, Kimura J, Miki Y, * Yoshida K
  • Journal Title: J Biol Chem 282 Pages: 33943-8
  • Peer Reviewed
• [Journal Article] Protein kinase C delta induces transcription of the TP53 tumor suppressor gene by controlling death-promoting factor Btf in the apoptotic response to DNA damage (2007)
  • Author(s): Liu H, Lu ZG, Miki Y, * Yoshida K
  • Journal Title: Mol Cell Biol 27 Pages: 8480-91
  • Peer Reviewed
• [Journal Article] Histological features of breast cancer, highly sensitive to chemotherapy (2007)
  • Author(s): Horii R, Akiyama F, Ito Y, Matsuura M, Miki Y, Iwase T
  • Journal Title: Breast Cancer 14 Pages: 393-400
  • NAID: 10019800584
  • Peer Reviewed
• [Journal Article] Interference with BRCA2, which localizes to the centrosome during S and early M Phase, leads to abnormal nuclear division. (2007)
  • Author(s): Nakanishi A, et. al.
  • Journal Title: Biochem Biophys Res Commun. 355 Pages: 34-40
  • Peer Reviewed
• [Journal Article] DYRK2 is targeted to the nucleus and controls p53 via Ser46 phosphorylation in the apoptotic response to DNA damage. (2007)
  • Author(s): Taira N, et. al.
  • Journal Title: Mol Cell. 25 Pages: 725-738
  • Peer Reviewed
• [Journal Article] Identification of novel deletion polymorphisms in breast cancer
  • Author(s): Komatsu, A., Nagasaki, K., Fujimori, M., Amano, J., and Miki, Y
  • Journal Title: Int J Oncol 33 Pages: 2008-2008
  • Peer Reviewed
• [Presentation] 乳癌診療標準化から個別化へ乳癌の化学療法感受性予測の試み (2008)
  • Author(s): 三木義男, 長崎光一, 牛嶋大, 松浦正明
  • Organizer: 第16回日本乳癌学会学術総会
  • Place of Presentation: 大阪
• [Presentation] 乳がん術前化学療法の効果予測システム開発の試み(Molecular prediction of the therapeutic response to neoadjuvant chemotherapy in breast cancer) (2008)
  • Author(s): 三木義男
  • Organizer: 第108回日本外科学会定期学術集会
  • Place of Presentation: 長崎
• [Presentation] 遺伝性の癌その研究と臨床の最前線 遺伝性乳癌卵巣癌が疑われる日本人を対象とするBRCA1/2遺伝子変異の横断的研究(Forefront of Basic and Clinical Researches in Hereditary Cancer Cross-sectional study of BRCA1 and BRCA2 mutations in Japanese patients suspected of hereditary breast/ovarian carcinoma) (2008)
  • Author(s): 菅野康吉, 中村清吾, 安藤二郎, 神野浩光, 池田正, 青木大輔, 福富隆志, 吉田輝彦, 新井正美, 平井康夫, 霞富士雄, 福井崇史, 三木義男
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋
• [Presentation] 乳がん基礎・病理・1次予防BRCA2-Plectin複合体は中心体の固定に関与する (2008)
  • Author(s): 三木義男, 丹羽隆善, 斉藤弘子, 中西啓
  • Organizer: 第14回日本家族性腫瘍学会学術集会
  • Place of Presentation: 東京
• [Presentation] アポトーシス誘導関連遺伝子の網羅的探索によるTAF1の同定と機能解析 (2008)
  • Author(s): 木村純子、グェンティエンスー、平直江、三木義男、吉田清嗣
  • Organizer: BMB2008
  • Place of Presentation: 神戸
• [Presentation] Pim-1はRelA/p65のリン酸化を介してNF-kBの活性化を制御する (2008)
  • Author(s): 仁平啓史、安藤雄祐、山口智子、三木義男、吉田清嗣
  • Organizer: BMB2008
  • Place of Presentation: 神戸
• [Presentation] ATMはDYRK2のリン酸化はキナーゼ活性を制御するとともに、MDM2を介したプロテアソーム系による分解からの回避を引き起こす (2008)
  • Author(s): 平直江、山本宙亨、山口智子、三木義男、吉田清嗣
  • Organizer: BMB2008
  • Place of Presentation: 神戸
• [Presentation] 乳癌の化学療法感受性予測の試み. (2008)
  • Author(s): 三木義男, 他
  • Organizer: 第16回日本乳癌学会学術総会
  • Place of Presentation: 大阪
• [Presentation] 乳がん術前化学療法の効呆予測システム開発の試み (2008)
  • Author(s): 三木義男
  • Organizer: 第108回日本外科学会定期学術集会
  • Place of Presentation: 長崎
• [Presentation] ATMによるDYRK2のリン酸化はキナーゼ活性を制御するとともに、MDM2による分解からの回避を引き起こす (2008)
  • Author(s): 平直江, 他
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋
• [Presentation] 新規BRCA2結合タンパク質BJ-HCC-20AはDNA損傷に応答したアポトーシス誘導を抑制する (2008)
  • Author(s): 冨吉郷, 他
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋
• [Presentation] アポトーシス誘導関連遣伝子の網羅的探索によるTAF1の同定と機能1 解析 (2008)
  • Author(s): 木村純子, 他
  • Organizer: BMB2008
  • Place of Presentation: 神戸
• [Presentation] 酸化ストレス下における、BRCA1およびpRbを介したubiquitinationによるtopoisomerase II αの活性阻害 (2007)
  • Author(s): 品川弘州等
  • Organizer: 第66回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2007-10-04
• [Presentation] 乳がんの分子遺伝学BRCAの機能と乳がん発生における役割(In the Forefront of Breast Cancer Research-Towards Steady Decrease of Cancer Mortality Breast cancer molecular biology and genetics : the role and function of BRCA1 and 2)(英語) (2007)
  • Author(s): 三木義男
  • Organizer: 第66回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] ゲノム、トランスクリプトーム情報の癌個別化治療への展開 (2007)
  • Author(s): 三木義男
  • Organizer: 第44回日本臨床分子医学会学術集会
  • Place of Presentation: 和歌山
• [Presentation] 非筋肉型ミオシンIICによる細胞質分裂の制御(Nonmuscle myosin IIC regulates the division of intercellular bridge of cytokinesis)(英語) (2007)
  • Author(s): 中西啓, 斉藤広子, 太田吉泰, 大海忍, 三木義男
  • Organizer: 第66回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] BRCA2と相互作用する新規蛋白質プレクチン(Plectin, a novel protein which interacts with BRCA2)(英語) (2007)
  • Author(s): 丹羽隆善, 中西啓, 大海忍, 上西紀夫, 三木義男
  • Organizer: 第66回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] BRCA2における機能的核輸送配列の同定(Identification of a Functional Nuclear Export Sequence in BRCA2)(英語) (2007)
  • Author(s): 韓香子, 中西啓, 斉藤広子, 三木義男
  • Organizer: 第66回日本癌学会学術総
  • Place of Presentation: 横浜
• [Presentation] DNA損傷に対するアポトーシス反応においてDYRK2は核を標的とし、Ser46リン酸化を介してp53を制御する(DYRK2 is Targeted to the Nucleus and Controlsp53 via Ser46 Phosphorylation in the ApoptoticResponse to DNA Damage)(英語) (2007)
  • Author(s): 平直江, 三木義男, 吉田清嗣
  • Organizer: 第66回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] 酸化ストレス下における、BRCA1およびpRbを介したubiquitinationによるtopoisomerase II alphaの活性阻害(BRCA1-mediated ubiquitination through pRb inhibits topoisomerase II alpha activity in response to oxidative stress)(英語) (2007)
  • Author(s): 品川弘州, 三木義男, 吉田清嗣
  • Organizer: 第66回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Book] がんの分子標的 (2008)
  • Author(s): 磯村実, 三木義男
  • Total Pages: 5
  • Publisher: 遣伝子多型解析
• [Remarks]
  • URL: http://www.tmd.ac.Jp/mri/mgen/index_j.html