Deciphering the mechanisms underlying cancer development induced by deregulation of proteolysis
Project/Area Number |
17013067
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Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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Allocation Type | Single-year Grants |
Review Section |
Biological Sciences
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Research Institution | Kyushu University |
Principal Investigator |
NAKAYAMA Keiichi Kyushu University, 生体防御医学研究所, 主幹教授 (80291508)
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Project Period (FY) |
2005 – 2009
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Project Status |
Completed (Fiscal Year 2009)
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Budget Amount *help |
¥47,600,000 (Direct Cost: ¥47,600,000)
Fiscal Year 2009: ¥8,800,000 (Direct Cost: ¥8,800,000)
Fiscal Year 2008: ¥8,800,000 (Direct Cost: ¥8,800,000)
Fiscal Year 2007: ¥10,000,000 (Direct Cost: ¥10,000,000)
Fiscal Year 2006: ¥10,000,000 (Direct Cost: ¥10,000,000)
Fiscal Year 2005: ¥10,000,000 (Direct Cost: ¥10,000,000)
|
Keywords | 細胞周期 / ユビキチン / タンパク質分解 / サイクリン / がん / p27 / c-Myc / ユビキチン化 / アポトーシス / Fbw7 / p53 / コンディショナルノックアウトマウス / KPC / プロテアソーム / Skp2 / 発がん / UBLドメイン / UBAドメイン |
Research Abstract |
Regulation of the exit of cells from the cell cycle is important in the development of multicellular organisms and is also implicated in the maintenance of stem cells. Furthermore, defects in cell cycle exit are thought to be a major cause of cancer. However, the mechanisms responsible for regulation of cell cycle exit have remained largely unknown. Fbw7 is the F-box protein subunit of an SCF-type ubiquitin ligase complex that targets positive regulators of the cell cycle including c-Myc for ubiquitylation and subsequent degradation by the 26S proteasome in order to promote cell cycle exit. Consistent with such a function, mutations of the Fbxw7 gene have been detected in various human malignancies. We have recently generated conventional and conditional Fbxw7 knockout mice and examined stem cells, progenitor cells, and differentiated cells in the mutant animals for cell cycle defects. Here we summarize the pleiotropic phenotypes of Fbxw7 deficiency in various cell types including T cells, hematopoietic stem cells, and embryonic fibroblasts. Such phenotypes have provided insight into the biological roles of Fbxw7 in cell cycle exit, stem cell maintenance, and oncosuppression.
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Report
(6 results)
Research Products
(55 results)
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[Journal Article] Skp2 targeting suppresses tumorigenesis by Arf-p53-independent cellular senescence2010
Author(s)
Lin, H.K., Chen, Z., Wang, G., Nardella, C., Lee, S.W., Chan, C.H., Yang, W.L., Wang, J., Egia, A., Nakayama, K.I., Cordon-Cardo, C., Teruya-Feldstein, J., Pandolfi, P.P.
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Journal Title
Nature 464
Pages: 374-379
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[Journal Article] Deciphering the transcriptional complex critical for RhoA gene expression and cancer metastasis2010
Author(s)
Chan, C.H., Lee, S.W., Li, C.F., Wang, J., Yang, W.L., Wu, C.Y., Wu, J., Nakayama, K.I., Kang, H.Y., Huang, H.Y., Hung, M.C., Pandolfi, P.P., Lin, H.K.
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Journal Title
Nature Cell Biol. (in press)
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[Journal Article] Skp2 is required for survival of aberrantly proliferating Rb1-deficient cells and for tumorigenesis in Rb1+/- mice2010
Author(s)
Wang, H., Bauzon, F., Ji, P., Xu, X., Sun, D., Locker, J., Sellers, R.S., Nakayama, K., Nakayama, K.I., Cobrinik, D., Zhu, L.
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Journal Title
Nature Genet 42
Pages: 83-88
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[Journal Article] CHD8 suppresses p53-mediated apoptosis through histone H1 recruitment during early embryogenesis2009
Author(s)
Nishiyama, M., Oshikawa, K., Tsukada, Y., Nakagawa, T., Iemura, S., Natsume, T., Fan, Y., Kikuchi, A., Skoultchi, A.I., Nakayama, K.I.
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Journal Title
Nature Cell Biol. 11
Pages: 172-182
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[Journal Article] Phosphorylation-dependent regulation of cytosolic localization and oncogenic function of Skp2 by Akt/PKB2009
Author(s)
Lin, H.K., Wang, G., Chen, Z., Teruya-Feldstein, J., Liu, Y., Chan, C.H., Yang, W.L., Erdjument-Bromage, H., Nakayama, K.I., Nimer, S., Tempst, P., Pandolfi, P.P.
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Journal Title
Nature Cell Biol 11
Pages: 420-432
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[Journal Article] Fbxo45 forms a novel ubiquitin ligase complex and is required for neuronal development2009
Author(s)
Saiga, T., Fukuda, T., Matsumoto, M., Tada, H., Okano, H.O., Okano, H., Nakayama, K.I.
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Journal Title
Molecular and Cellular Biology 29
Pages: 3529-3543
Related Report
Peer Reviewed
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[Journal Article] Conditional inactivation of Fbxw7 impairs cell-cycle exit during T cell differentiation and results in lymphomatogenesis2007
Author(s)
Onoyama, I., Tsunematsu, R., Matsumoto, A., Kimura, T., de Alboran, I.M., Nakayama, K., Nakayama, K.I.
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Journal Title
J. Exp. Med. 204
Pages: 2875-2888
Related Report
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[Journal Article] Mitogenic signalling and the p16INK4a-Rb pathway cooperate to enforce irreversible cellular senescence2006
Author(s)
Takahashi, A., Ohtani, N., Yamakoshi, K., Iida, S., Tahara, H., Nakayama, K., Nakayama, K.I., Ide, T., Saya, H., Hara, E.
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Journal Title
Nature Cell Biol. 8
Pages: 1291-1297
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[Journal Article] Fbxw8 is essential for Cull-Cul7 complex formation and for placental development.2006
Author(s)
Tsunematsu, R., Nishiyama, M., Kotoshiba, S., Saiga, T., Kamura, T., Nakayama, K.I.
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Journal Title
Mol. Cell. Biol. 26
Pages: 6157-6169
Related Report
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[Journal Article] Mitogenic signalling and the p16^<INK4a>-Rb pathway cooperate to enforce irreversible cellular senescence.2006
Author(s)
Takahashi, A., Ohtani, N., Yamakoshi, K., Iida, S., Tahara, H., Nakayama, K., Nakayama, K.I., Ide, T., Saya, H., Hara, E.
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Journal Title
Nature Cell Biol. 8
Pages: 1291-1297
Related Report
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