Elucidation of mechanisms underlying p53-independent growth-suppressive activity for tumor suppressor proteins with p53-activating function.
| Project/Area Number |
15590281
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pathological medical chemistry
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| Research Institution | Keio University |
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Principal Investigator |
MATSUOKA Masaaki Keio University, Department of Medicine, Associate Professor, 医学部, 助教授 (70222297)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2004: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2003: ¥1,900,000 (Direct Cost: ¥1,900,000)
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| Keywords | p53 / ik3-1 / ik3-2 / ARF / BCL6 / CR / Cdc7 / BAX |
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| Research Abstract |
1)ARF-mediated p53-independent tumor suppression occurs in part through BCL6.
The ARF tumor' suppressor gene antagonizes generation of various tumors. ARF-mediated tumor suppression occurs in a p53-independent manner as well as in a p53-dependent manner. In this study, we demonstrate that BCL6 is a target of the ARF tumor suppressor. Either mouse p19^<ARF> or human p14^<ARF> binds to BCL6 and downregulates BCL6-induced transcriptional repression. The N-terminal 37 amino acids of p19^<ARF> are necessary and sufficient for ARF-mediated downregulation of BCL6 transcriptional repression. Thus, we have concluded that ARF-mediated downregulation of the BCL6 activity may account in part for ARF-mediated tumor suppression. In addition, we have found that Bax is the main mediator of ARF-induced p53-independent apoptosis.
2)p53-independent apoptosis induced by ik3-1/ik3-2 is mediated in part by mediated by CR.
CR(Cdc7 expression repressor)/periphilin has been originally cloned as an interactor with periplakin, a precursor of the cornified cell envelope, and suggested to constitute a new type of nuclear matrix. We have found that CR/periphilin is a ubiquitously expressed nuclear protein with speckled distribution. Overexpression of CR/periphiilin induces S-phase arrest. Analysis of expression of regulators involved in DNA replication, has revealed that both mRNA and protein expression of Cdc7, a regulator of the initiation and continuation of DNA replication, are markedly downregulated by overexpression of CR/periphilin. In addition, we have found that CR associates with histone deacetylase I and mSin3A that act as co-reppressors for various transcriptional reppressors, suggesting that CR is also a co-repressor. In conclusion, it appears that CR mediates p53-independent apoptosis induced by ik3-1/ik3-2 by acting as a transcriptional co-repressor.
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Report
(3 results)
Research Products
(38 results)
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[Journal Article] Neuroprotedive effect of activity-dependent neurotrophic factor against toxicity from familial amyotrophic lateral sclerosis-linked mutant SODi in vitro and in vivo.2004
Author(s)
Chiba T, Hashimoto Y, Tajima H, Yamada M, Kato R, Niikura T, Terashita K, Schulman H, Aiso S, Kita Y, Matsuoka M, Nishimoto I.
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Journal Title
J.Neurosci.Res. 78
Pages: 542-552
Description
「研究成果報告書概要(欧文)」より
Related Report
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[Journal Article] Targeted introduction of V6421 mutation in amyloid precursor protein gene causes functional abnormality resembling early stage of Alzheimer's disease in aged mice.2004
Author(s)
Kawasumi M, Chiba T, Yamada M, Miyamae-Kaneko M, Matsuoka M Nakahara I, Tomita T, Iwatsubo T, Kato S, Aiso S, Nishimoto I, Kouyama K.
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Journal Title
Eur.J.Neurosci. 19
Pages: 2826-2838
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Analysis of neurons created from wild-type and Alzheimer's mutation knock-in embryonic stem cells by a highly efficient differentiation protocol.2003
Author(s)
Abe Y, Kouyama K, Tomita T, Tomita Y, Ban N, Nawa M, Matsuoka M, Niikura T, Aiso S, Kita Y, Iwatsubo T, Nishimoto I.
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Journal Title
J.Neurosci. 23
Pages: 8513-8525
Description
「研究成果報告書概要(欧文)」より
Related Report
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[Publications] Abe Y, Kouyama K, Tomita T, Tomita Y, Ban N, Nawa M, Matsuoka M, Niikura T, Aiso S, Kita Y, Iwatsubo T, Nishimoto I.: "Analysis of neurons created from wild-type and Alzheimer's mutation knock-in embryonic stem cells by a highly efficient differentiation protocol."J.Neurosci. 23. 8513-8519 (2003)
