2005 Fiscal Year Final Research Report Summary
| Project/Area Number |
13043005
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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 | The University of Tokyo |
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Principal Investigator |
OKAYAMA Hiroto The University of Tokyo, Graduate School of Medicine, Professor, 大学院医学研究科, 教授 (40111950)
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| Co-Investigator(Kenkyū-buntansha) |
SAGATA Noriyuki Kyushu University, Faculty of Science, Professor, 大学院理学研究院, 教授 (80142024)
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| Project Period (FY) |
2001 – 2005
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| Keywords | Control of S phase onset / Anchorage-dependent and independent proliferation / Cdc6 / p53 / Tsc-Rheb / Cdc25A / Uniquitvlation |
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| Research Abstract |
We have made considerable progress in understanding the mechanism of anchorage-dependent and independent cell cycle onset, the basis for the ability of malignantly transformed cells to make tumor formation and metastasis. The following is the key findings made. 1. Upon anchorage loss, expression of Cdc6 the initiator of chromosomal replication is terminated by both promoter shutdown and by facilitated proteolysis. 2. Two ubiquitin ligases and one cathepsins-like cysteine protease are responsible for this proteolysis. 3. One of the ligases is Cdhl-APC known to degrade Cdc6 in Gl, but we found requires p53 recessive oncoprotein for its function. 4. The degradation of Cdc6 by these systems appears to be regulated by signals mediated by Tsc-Rheb linked to PI3K and mTOR. In addition, we have found that a particular combination of cyclin Ds and their partner kinases, Cdk6/D3 evades inhibitions by inhibitor proteins and consequently has a unique ability to promote cell proliferation under growth suppressive conditions, and seemingly therefore enhance susceptibility of cells to chemically induced malignant transformation.
On the other hands, we have made progress in understanding the molecular mechanism involved in the regulation of cyclin-dependent kinases by tyrosine phosphorylation and discovered the occurrence of the phosphorylation-independent DDG motif in Cdc25A, which is recognized by TrCP-SCFb that is known to recognize such a motif only after being phosphorylated.
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Research Products
(27 results)
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[Journal Article] Nonviral gene delivery by tetraamino fullerene.2006
Author(s)
Isobe, H., Nakanishi, W., Tomita, N., Jinno, S., Okayama, H., Nakamura, E.
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Journal Title
Mol. Pharm. 3(2)
Pages: 124-134
Description
「研究成果報告書概要(和文)」より
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[Journal Article] Inhibition of Cdk6 expression through p38 MAP kinase is involved in differentiation of mouse prechondrocyte ATDC5.2005
Author(s)
Moro, T., Ogasawara, T., Chikuda, H., Ikeda, T., Ogata, N., Maruyama, Z., Komori, T., Hoshi, K., Chung, U.I., Nakamura, K., Okayama, H., Kawaguchi H.
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Journal Title
J. Cell Physiol. 204
Pages: 927-933
Description
「研究成果報告書概要(和文)」より
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[Journal Article] Osteoclast differentiation by RANKL requires NF-kappaB-mediated downregulation of cyclin-dependent kinase 6 (Cdk6).2004
Author(s)
Ogasawara, T., Katagiri, M., Yamamoto, A., Hoshi, K., Takato, T., Nakamura, K., Tanaka, S., Okayama, H., Kawaguchi, H.
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Journal Title
J. Bone Miner. Res. 19
Pages: 1128-1136
Description
「研究成果報告書概要(和文)」より
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[Journal Article] Bone morphogenetic protein-2-induced osteoblast differentiation requires Smad-mediated down-regulation of Cdk62004
Author(s)
Ogasawara, T., Kawaguchi, H., Jinno, S., Hoshi, K., Itaka, K., Takato, T., Nakamura, K., Okayama, H.
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Journal Title
Mol. Cell. Biol. 24
Pages: 6560-6568
Description
「研究成果報告書概要(和文)」より
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[Journal Article] Chk1, but not Chk2, inhibits Cdc25 phosphatases by a novel common mechanism.2004
Author(s)
Uto, K., Inoue, D., Shimuta, K., Nakajo, N., Sagata, N.
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Journal Title
EMBO J. 23
Pages: 3386-3396
Description
「研究成果報告書概要(和文)」より
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[Journal Article] Bone morphogenetic protein-2-induced osteoblast differentiation requires Smad-mediated down-regulation of Cdk6.2004
Author(s)
Ogasawara, T., Kawaguchi, H., Jinno, S., Hoshi, K., Itaka, K., Takato, T., Nakamura, K., Okayama, H.
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Journal Title
Mol. Cell. Biol. 24
Pages: 6560-6568
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Chkl, but not Chk2, inhibits Cdc25 phosphatases by a novel common mechanism.2004
Author(s)
Uto, K., Inoue, D., Shimuta, K., Nakajo, N., Sagata, N.
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Journal Title
EMBO J. 23
Pages: 3386-3396
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Mammalian Rcd1 is a novel transcriptional cofactor that mediates retinoic acid-induced cell differentiation.2002
Author(s)
Hiroi, N., Ito, T., Yamamoto, H., Ochiya, T., Jinno, S., Okayama, H.
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Journal Title
EMBO J. 21
Pages: 5235-5244
Description
「研究成果報告書概要(和文)」より
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[Journal Article] Mammalian Rcdl is a novel transcriptional cofactor that mediates retinoic acid-induced cell differentiation.2002
Author(s)
Hiroi, N., Ito, T., Yamamoto, H., Ochiya, T., Jinno, S., Okayama, H.
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Journal Title
EMBO J. 21
Pages: 5235-5244
Description
「研究成果報告書概要(欧文)」より
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