Systems biological analysis of dynamic regulation of stem cells and development by growth factors

2010 Fiscal Year Final Research Report

• Project/Area Number: 20390075
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: The University of Tokyo
• Principal Investigator: GOTOH Noriko The University of Tokyo, 医科学研究所, 特任准教授 (10251448)
• Co-Investigator(Kenkyū-buntansha): MIYANO Satoru 東京大学, 医科学研究所, 教授 (50128104)
• Project Period (FY): 2008 – 2010
• Keywords: 細胞・組織 / シグナル伝達 / マイクロアレイ / 発生・分化 / システム生物学

Research Abstract

We aimed to clarify molecular mechanisms how growth factors regulate self-renewing activity of tissue type specific stem cells by using novel bioinfomatics. As a result, we identified Hes1 as a key molecular target of self-renewal of neural stem cells and FRS2alpha-Shp2-Tbx2 pathway as a key pathway for development of cardiac progenitor cells. Moreover, we identified NFkB as a key molecular target for self-renewing mammalian stem cells as well as breast cancer stem cells.

Research Products

• [Journal Article] Somatic mutations of the EGF receptor and their signal transducers affect the efficacy of EGF receptor-specific tyrosine kinase inhibitors. (2011)
  • Author(s): Gotoh, N.
  • Journal Title: Int.J.Clin.Exp.Pathol. 4 Pages: 403-409
• [Journal Article] Integrated quantitative analysis of the phosphoproteome and transcriptome in tamoxifen-resistant breast cancer. (2010)
  • Author(s): Oyama, M., Nagashima, T., Suzuki, T., Kozuka-Hata, H., Yumoto, N., Shiraishi, Y., Ikeda, K., Kuroki, Y., Gotoh, N., Ishida, T., Inoue, S., Kitano, H., Okada-Hatakeyama, M.
  • Journal Title: J.Biol.Chem. 286 Pages: 818-829
• [Journal Article] Phosphoproteomics-based modeling defines the regulatory mechanism underlying aberrant EGFR signaling. (2010)
  • Author(s): Tasaki, S., Nagasaki, M., Kozuka-Hata, H., Semba, K., Gotoh, N., Hattori, S., Inoue, J., Yamamoto, T., Miyano, S., Sugano, S., Oyama, M.
  • Journal Title: PLoS ONE 5(11) Pages: e13926
• [Journal Article] Inflammatory signaling pathways in self-renewing breast cancer stem cells. (2010)
  • Author(s): Hinohara, K., Gotoh, N.
  • Journal Title: Curr.Opin.Pharmacol. 10 Pages: 650-654
• [Journal Article] Collocation-based sparse estimation for constructing dynamic gene networks. (2010)
  • Author(s): Shimamura, T., Imoto, S., Nagasaki, M., Yamauchi, M., Yamaguchi, R., Fujita, A., Tamada, Y., Gotoh, N., Miyano, S.
  • Journal Title: Genome Inform. 24 Pages: 164-178
• [Journal Article] FGF-FRS2α-Erk axis controls a self-renewal target Hes1 and growth of neural stem/progenitor cells. (2010)
  • Author(s): Sato, T., Shimazaki, T., Naka, H, Fukami, S., Okano, H., Lax, I., Schlessinger, J., Gotoh, N.
  • Journal Title: Stem Cells. 28 Pages: 1661-1672
• [Journal Article] A state space representation of VAR models with sparse learning for dynamic gene networks. (2010)
  • Author(s): Kojima, K., Yamaguchi, R., Imoto, S., Yamauchi, M., Nagasaki, M., Yoshida, R., Shimamura, T, Ueno, K., Higuchi, T.,, Gotoh, N., Miyano, S.
  • Journal Title: Genome Inform. 22 Pages: 56-68
• [Journal Article] FRS2β, a potential prognostic gene for non-small cell lung cancer, encodes a feedback inhibitor for EGF receptor family members via ERK binding. (2010)
  • Author(s): Iejima, D., Minegichi, Y., Takenaka, K., Siswanto, A., Watanabe, M., Huang, L., Watanabe, T., Tanaka, F., Kuroda, M., Gotoh, N.
  • Journal Title: Oncogene 29 Pages: 3087-3099
• [Journal Article] Gene set enrichment analysis provides insight into novel signaling pathways in breast cancer stem cells. (2010)
  • Author(s): Murohashi, M., Hinohara, K., Kuroda, M., Isagawa, T., Tsuji, S., Kobayashi, S., Umezawa, K., Tojo, A., Aburatani, H., Gotoh, N.
  • Journal Title: British J.Cancer 102 Pages: 206-212
• [Journal Article] An FGF4-FRS2α-Cdx2 axis-in trophoblast stem cells induces BMP4 to regulate proper growth of early mouse embryos. (2010)
  • Author(s): Murohashi, M., Nakamura, T., Tanaka, S., Ichise, T., Yoshida, N., Yamamoto, T., Shibuya, M., Schlessinger, J., Gotoh, N.
  • Journal Title: Stem Cells 28 Pages: 113-121
• [Journal Article] Gain-of-function of mutated c-Cbl tumor suppressor in myeloid neoplasms with 11q uniparental disomy. (2009)
  • Author(s): Sanada, M., Suzuki, T., Shih, L.-Y., Otsu, M., Kato, M., Yamazaki, S., Tamura, A., Honda, H., Sakata-Yanagimoto, M., Kumano, K., Oda, H., Yamagata, T., Takita, J., Gotoh, N., Nakazaki, K., Kawamata, N., Onodera, M., Nobuyoshi, M., Hayashi, Y., Harada, H., Kurokawa, M., Chiba, S., Mori, H., Ozawa, K., Omine, M., Hirai, H., Nakauchi, H., Koeffler, P., Ogawa, S.
  • Journal Title: Nature 460 Pages: 904-909
• [Journal Article] FRS2βdocking/scaffolding adaptor protein. (2009)
  • Author(s): Iejima, D., Gotoh, N.
  • Journal Title: Current research in cancer, Research Media, India 3 Pages: 99-107
• [Journal Article] FRS2alpha is required for the separation, migration, and survival of pharyngeal-endoderm derived organs including thyroid, ultimobranchial body, parathyroid, and thymus. (2009)
  • Author(s): Kameda, Y., Ito, M., Nishimaki, T., Gotoh, N.
  • Journal Title: Dev.Dyn. 238 Pages: 503-513
• [Journal Article] Molecular mechanisms determining efficacy of EGF receptor-specific tyrosine kinase inhibitors help to identify biomarker candidates. (2009)
  • Author(s): Yamauchi, M., Gotoh, N.
  • Journal Title: Biomark.Med. 3 Pages: 139-151
• [Journal Article] Frs2beta. (2009)
  • Author(s): Minegishi, Y., Gotoh, N.
  • Journal Title: Nature Molecule Pages Pages: doi:10.1038/mp.a004122.01
• [Journal Article] Prominent expression of FRS2β protein in neural cells and its association with intracellular vesicles. (2009)
  • Author(s): Minegishi, Y., Iwanari, H., Mochizuki, Y., Horii, T., Hoshino, T., Kodama, T., Hamakubo, T., Gotoh, N.
  • Journal Title: FEBS lett. 583 Pages: 807-814
• [Journal Article] The FRS2 family of docking/scaffold adaptor proteins as therapeutic targets of cancer treatment. (2009)
  • Author(s): Sato T., Gotoh, N.
  • Journal Title: Expert Opinion on Therapeutic Targets 13 Pages: 689-700
• [Journal Article] Frs2alpha. (2009)
  • Author(s): Sato, T., Gotoh, N.
  • Journal Title: Nature Molecule Pages Pages: doi:10.1038/mp.a000967.01
• [Journal Article] Control of stemness by fibroblast growth factor signaling in stem cells and cancer stem cells. (2009)
  • Author(s): Gotoh, N.
  • Journal Title: Current Stem Cell Research & Therapy 4 Pages: 9-15
• [Journal Article] Feedback inhibitors of epidermal growth factor receptor signaling pathways. (2009)
  • Author(s): Gotoh, N.
  • Journal Title: Int.J.Biochem.Cell Biol. 41 Pages: 511-515
• [Journal Article] Predicting differences in gene regulatory systems by state space models. (2008)
  • Author(s): Yamaguchi, R., Imoto, S., Yamauchi, M., Nagasaki, M., Yoshida, R., Shimamura, T., Hatanaka, Y., Ueno, K., Higuchi, T., Gotoh, N., Miyano, S.
  • Journal Title: Genome Infomatics 21 Pages: 101-113
• [Journal Article] Regulation of growth factor signaling by FRS2 family docking/scaffold adaptor proteins. (2008)
  • Author(s): Gotoh, N.
  • Journal Title: Cancer Sci. 99 Pages: 1319-1325
• [Journal Article] FRS2α^<2F/2F> mutant mice lack the carotid body and exhibit sympathetic ganglia and carotid sinus nerve abnormalities. (2008)
  • Author(s): Kameda, Y., Ito, M., Nishimaki T., Gotoh, N.
  • Journal Title: Dev.Biol. 314 Pages: 236-247
• [Journal Article] Membrane-linked docking protein.Encyclopedia of Cancer (2008)
  • Author(s): Gotoh, N., Tsuchida, N.
  • Journal Title: 2^<nd> Edition, Springer, Heidelberg, Germany Pages: 1819-1823
• [Journal Article] A genetic study of the effects of reduced Frs2alpha gene dosage in exostoses development and cartilage abnormalities observed in Ext2 heterozygous mutant mice.
  • Author(s): Nasirujjaman K., Kimura-Yoshida, C., Gotoh, N., Hiramatsu, R., Matsuo I.
  • Journal Title: Journal of Osaka Medical Center & Research Institute for Maternal & Child Health. in press
• [Presentation] 新規バイオインフォマティクス手法を用いた癌幹細胞内シグナル伝達経路の解明"創薬薬理フォーラム (2010)
  • Author(s): 後藤典子
  • Organizer: 第18回シンポジウム
  • Place of Presentation: 東京 招待講演
  • Year and Date: 20100900
• [Presentation] 腫瘍抑制候補アダプタータンパクFRS2betaはCIN85/CD2APと結合しErbB2シグナルを減弱化する (2010)
  • Author(s): 峯岸ゆり子、服部成介、後藤典子
  • Organizer: 第69回日本癌学会学術総会
  • Place of Presentation: 大阪 口演
  • Year and Date: 20100900
• [Presentation] A key role of NF-kB pathway in breast cancer stem cells for tumorigenesis. (2009)
  • Author(s): 後藤典子
  • Organizer: 14^<th> World Congress on Advances in Oncology and 12^<th> International Symposium on Molecular Medicine
  • Place of Presentation: Loutraki, Greece 招待講演
  • Year and Date: 20091015-20091017
• [Presentation] Biology Division, National Cancer Center Research Institute, Tokyo, Japan (2009)
  • Author(s): 峯岸ゆり子、服部成介、後藤典子
  • Organizer: Exploration of new biomarkers and molecular targets of lung carcinoma by systems biology approach 68^<th> Annual Meeting of the Japanese Cancer Association 第68回日本癌学会学術総会
  • Place of Presentation: 横浜 招待講演
  • Year and Date: 20091001-20091003
• [Presentation] Growth factor signaling systems idenfiy critical genes for survival prediction in lung adenocarcinoma (2009)
  • Author(s): 後藤典子
  • Organizer: The 16^<th> East Asia Joint conference on Biomedical Research
  • Place of Presentation: 京都 招待講演
  • Year and Date: 20090913-20090914
• [Book] Encyclopedia of Signaling Molecules.Springer(FRS2.), Germany.
  • Author(s): Gotoh, N.
  • Publisher: Heidelberg
• [Book] Cancer Stem Cells(Possible signaling pathways in cancer stem cells in breast cancer.)(Nikolic, A.(Ed.))Austria.
  • Author(s): Gotoh, N.
  • Publisher: ITECH, Vienna
• [Patent(Industrial Property Rights)] 癌の予後を予測するためのバイオマーカー (2009)
  • Inventor(s): 後藤典子、山内麻衣、宮野悟、井元清哉、山口類、横田淳、河野隆志
  • Industrial Property Number: PCT/JP2009/70386
  • Filing Date: 2009-12-04
  • Overseas
• [Patent(Industrial Property Rights)] 固形癌の再発予測のための試験方法及び再発予防剤 (2009)
  • Inventor(s): 後藤典子、室橋道子、油谷浩幸、砂河孝行、黒田雅彦
  • Industrial Property Number: 特願2009-023933
  • Filing Date: 2009-02-04
• [Patent(Industrial Property Rights)] 癌の予後を予測するためのバイオマーカー (2008)
  • Inventor(s): 後藤典子、山内麻衣、宮野悟、井元清哉、山口類、横田淳、河野隆志
  • Industrial Property Number: 特願2008-311481
  • Filing Date: 2008-12-05