2009 Fiscal Year Final Research Report
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 |
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| Review Section |
Biological Sciences
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| Research Institution | Kyushu University |
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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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| Keywords | 細胞周期 / ユビキチン / タンパク質分解 / サイクリン / がん |
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| 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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[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] 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
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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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