2004 Fiscal Year Final Research Report Summary
Investigation into the molecular mechanisms underlying proteolysis of CDK inhibitor p27
| Project/Area Number |
12213097
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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, Medical Institute of Bioregulation, Department of Molecular and Cellular Biology, Professor, 生体防御医学研究所, 教授 (80291508)
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| Project Period (FY) |
2000 – 2004
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| Keywords | Cell Cycle / CDK inhibitor / p27 / ubiquitin / SCF complex / Skp2 / KPC |
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| Research Abstract |
We have studied the mechamism underlying the regulation of the abundance of the CDK inhibitor p27. p27 is degraded at the GO-G1 transition, and its abundance remains low during cell proliferation. The SCF/Skp2 ubiquitin ligase complex has been thought to play a critical role in p27 degradation. However, analysis of Skp2-deficient mice revealed that degradation of p27 at the GO-G1 transition proceeds normally in Skp2-/-cells, whereas p27 proteolysis during S-G2 phases is impaired in these Skp2-deficient cells. These results suggested the presence of Skp2-independent pathway to control ubiquitination of p27 at the GO-G1 transition. Using in vitro ubiquitylation assay, we biochemically purified a complex consisting of two proteins, designated KPC (Kip1 ubiquitylation Promoting Complex)1 and KPC2. Given that KPC1/2 are localized in the cytoplasm, nuclear export of p27 seems to precede the ubiquitination by KPC1/2. Overexpression of wild-type KPC1/2 in mammalian cells promotes the degradation of p27, whereas expression of dominant-negative mutant KPC 1/2 delayed the degradation. Depletion of KPC1 by RNA interference also inhibited p27 degradation. These data suggest that KPC 1/2 ubiquitin ligase complex controls the degradation of p27 at the GO-G1 transition, whereas the major function of Skp2 may be the regulation of progression from G2 to M phase by mediating the degradation of p27.
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[Journal Article] Cytoplasmic ubiquitin ligase KPC regulates proteolysis of p27^<Kip1> at G1 phase.2004
Author(s)
Kamura, T., Hara, T., Matsumoto, M., Ishida, N., Okumura, F., Hatakeyama, S., Yoshida, M., Nakayama, K., Nakayama, K.I.
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Journal Title
Nature Cell Biol. 6
Pages: 1229-1235
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] VHL-box and SOCS-box domains determine binding specificity for Cul2-Rbx1 and Cul5-Rbx2 modules of ubiquitin ligases.2004
Author(s)
Kamura, T., Maenaka, K., Kotoshiba, S., Matsumoto, M., Kohda, D., Conaway, R.C., Conaway, J.W., Nakayama, K.I.
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Journal Title
Genes Dev. 18
Pages: 3055-3065
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Skp2-mediated degradation of p27 regulates progression into mitosis.2004
Author(s)
Nakayama, K., Nagahama, H., Minamishima, Y.A., Miyake, S., Ishida, N., Hatakeyama, S., Kitagawa, M., Iemura, S., Natsume, T., Nakayama, K.I.
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Journal Title
Dev.Cell 6
Pages: 661-672
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Phosphorylation- dependent degradation of c-Myc is mediated by the F-box protein Fbw7.2004
Author(s)
Yada, M., Hatakeyama, S., Kamura, T., Nishiyama, M., Tsunematsu, R., Imaki, H., Ishida, N., Okumura, F., Nakayama, K., Nakayama, K.I.
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Journal Title
EMBO J. 23
Pages: 2116-2125
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Degradation of p57^<Kip2> mediated by SCF^<skp2>-dependent ubiquitylation.2003
Author(s)
Kamura, T., Hara, T., Kotoshiba, S., Yada, M., Ishida, N., Imaki, H., Hatakeyama, S., Nakayama, K., Nakayama, K.I.
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Journal Title
Proc.Natl.Acad.Sci.USA 100
Pages: 10231-10236
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Impaired degradation of inhibitory subunit of NF-KB (IKB) and 3- catenin as a result of targeted disruption of the p-TrCP1 gene.2003
Author(s)
Nakayama, K., Hatakeyama, S., Maruyama, S., Kikuchi, A., Onoe, K., Good, R.A., Nakayama, K.I.
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Journal Title
Proc.Natl.Acad.Sci.USA 100
Pages: 8752-8757
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Increased proliferation of B cells and auto-immunity in mice lacking protein kinase Co.2002
Author(s)
Miyamoto, A., Nakayama, K., Imaki, H., Hirose, S., Jiang, Y., Abe, M., Tsukiyama, T., Nagahama, H., Ohno, S., Hatakeyama, S., Nakayama, K.I.
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Journal Title
Nature 416
Pages: 865-869
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Aberrant cell cycle checkpoint function and early embryonic death in Chk1^<-/-> mice.2000
Author(s)
Takai, H., Tominaga, K., Motoyama, N., Minamishima, Y.A., Nagahama, H., Tsukiyama, T., Ikeda, K., Nakayama, K., Nakanishi, N., Nakayama, K.I.
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Journal Title
Genes Dev. 14
Pages: 1439-1447
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Targeted disruption of Skp2 results in accumulation of cyclin E and p27^<kip1>, polyploidy and centrosome overduplication.2000
Author(s)
Nakayama, K., Nagahama, H., Minamishima, Y.A., Matsumoto, M., Nakamichi, I., Kitagawa, K., Shirane, M., Tsunematsu, R., Tsukiyama, T., Ishida, N., Kitagawa, M., Nakayama, K.I., Hatakeyama, S.
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Journal Title
EMBO J. 19
Pages: 2069-2081
Description
「研究成果報告書概要(欧文)」より
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