| 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)
石見 幸男 三菱化学生命科学研究所, 生命分子工学部, 主任研究員
白髭 克彦 理化学研究所, 横浜研究所, 研究員
大矢 禎一 東京大学, 大学院・新領域創成科学研究科, 教授 (20183767)
石見 幸夫 三菱化学, 生命科学研究所, 主任研究員
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| Project Period (FY) |
2001 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥151,600,000 (Direct Cost: ¥151,600,000)
Fiscal Year 2005: ¥25,300,000 (Direct Cost: ¥25,300,000)
Fiscal Year 2004: ¥24,700,000 (Direct Cost: ¥24,700,000)
Fiscal Year 2003: ¥33,500,000 (Direct Cost: ¥33,500,000)
Fiscal Year 2002: ¥35,000,000 (Direct Cost: ¥35,000,000)
Fiscal Year 2001: ¥33,100,000 (Direct Cost: ¥33,100,000)
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| Keywords | Control of S phase onset / Anchorage-dependent and independent proliferation / Cdc6 / p53 / Tsc-Rheb / Cdc25A / Uniquitvlation / 足場非依存性増殖 / カテプシン / リソゾーム / Cdk6 / Cdk4 / 骨分化 / BMP-2 / Smad / Chk1 / DNA障害・複製チェックポイント / 細胞周期 / G1 / S / S.pombe / Cdc2 / チェックポイント / D3 |
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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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