Destabilization of RAG proteins and cell cycle regulation by Polycomb group genes
| Project/Area Number |
09670330
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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 |
Immunology
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| Research Institution | HIROSHIMA UNIVERSITY |
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Principal Investigator |
KANNO Masamoto Faculty of Medicine, HIROSHIMA UNIVERSITY Professor, 医学部, 教授 (40161393)
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| Project Period (FY) |
1997 – 1998
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| Project Status |
Completed (Fiscal Year 1998)
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| Budget Amount *help |
¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 1998: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 1997: ¥2,400,000 (Direct Cost: ¥2,400,000)
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| Keywords | Lymphoid differentiation / Polycomb group gene / Cell cycle / Cell death / Transcriptional regulation / RAG protein / ポリコム遺伝子群 / RAG2蛋白質 |
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| Research Abstract |
Polycomb group (PcG) genes are known as negative regulators of the transcriptional memory mechanisms via chromatin silencing in Drosophila. They ensure the maintenance of transcription patterns of key regulators such as homeotic genes which were involved in the dictation of body plan, however the other functions and target genes were not well investigated to date. mel-18 is a mammalian homologue of Drosophila PcG gene posterior sex combs and encodes a transcriptional repressor with tumor suppressive activity. Here we found that mice overexpressing mel-18 showed a cell cycle arrest of mature B-cells on B-cell receptor (BCR) stimulation with downregulation of c-myc. Molecular analysis revealed that the downregulation of cyclinD2, cyclinE, CDK4, CDK6 , CDK7, and CDC25A causes the impaired activities of cyclin-dependent kinases, resulting in hypophosphorylation of the retinoblastoma protein. Vise versa, the upregulation of c-MYC, CDC25 and CDC2/CDK2 kinase activities resulted in augmentation of proliferation of B-cells in mel-18 deficient mice. c-Myc is known to regulate positively the expression of cdc25a. Thus we propose that mel-18 negatively regulates the cell cycle progression at least through a cascades leading to c-myc then cdc25a. We will also discuss that the defect in lymphocyte development of mel-18 deficient mice implies the involvement of mel-18 in the maintenance of immature lymphocyte by regulating their susceptibility to cell death. More recently we found the spontaneous tumorigenesis in aged mel-18+/- mice. Therefore we would like to propose that PcG genes are the regulators to control the balance between proliferation and cell deathin lympoid cell, hence in prospects of applications to prevention, diagnosis and therapy of immunological disease.
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Report
(3 results)
Research Products
(15 results)
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[Publications] etsu, O., Ishihara, H., Kanno, R., Kamiyasu, M., Inoue, H., Tokuhisa, T., Taniguchi, M.and Kanno, M.: "mel-18 negatively regulates cell cycle progression upon B cell antigen receptor stimulation through a cascade leading to c-myc/cdc25." Immunity.9. 439-448 (1998)
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[Publications] Hasegawa, M., Tetsu, O., Kanno, R., Inoue, H., Ishihara, H., Kamiyasu, M., Taniguchi, M.and Kanno, M.: "Mammalian Polycomb group genes are categorized as new type of early response gene induced by B-cell receptor cross linking." Molecular Immunology. 35. 559-563 (1998)
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[Publications] Cui, J., Shin, T., Kawano, T., Sato, H., Kondo, E., Toura, I., Kaneko, Y., Koseki, H., Kanno, M., Taniguchi, M.: "Requirement for Valpha14NKT cells in IL-12-mediated rejection of tumors." Science. 278. 1623-1626 (1997)
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[Publications] Akasaka, T., Tsuji, K-I., Kawahira, H., Kanno, M., Harigaya, K-I., Hu, L., Ebihara, Y., Nakahata, T., Tetsu, O., Taniguchi, M.and Koseki, H.: "The role of mel-18, a mammalian Polycomb group gene, during IL-7-dependent proliferation of lymphocyte precursors." Immunity. 7. 135-146 (1997)
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