1997 Fiscal Year Final Research Report Summary
Role of tumor suppressor IRF-1 in the regulation of cell proliferation and oncogenesis.
| Project/Area Number |
07670172
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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 | Graduate School of Medicine, University of Tokyo (1996-1997)
Nara Institute of Science and Technology (1995) |
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Principal Investigator |
TANAKA Nobuyuki University of Tokyo, Graduate School of Medicine, Associate Professor, 大学院医学系研究科, 助教授 (80222115)
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| Project Period (FY) |
1995 – 1997
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| Keywords | IRF-1 / interferon / oncogenesis / apoptosis / cell cycle / p21 / p53 / NPM |
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| Research Abstract |
The transcriptional activator IRF-1 was originally identified as a regulator of the interferon system. We have previously demonstrated that that IRF-1 acts as a tumor suppressor and a regulator of cell cycle and apoptosis. To investigate further the role of IRF-1 in the regulation of cell cycle and apoptosis, we analyzed the cellualar responses to DNA damage in cells from mice lacking IRF-1.
We observed that DNA damage-induced apoptosis in mitogen-activated mature Tlymphocytes but not in thymocytes is dependent IRF-1, and that mitogen induction of the Caspace-1 gene IRF-1-dependent. On the other hand, the tumor suppressor p53 regulates apoptosis in thymocytes, but not in mitogen-activated mature Tlymphocytes. Thus two different anti-oncogenic transcription factors, IRF-1 and p53, are required for distinct apoptotic pathways in Tlymphocytes.
In the case of fibroblasts DNA-damage induces cell cycle arrest but not apoptosis. We observed that IRF-1 lacking EFs are deficient in their ability
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to undergo DNA damage-induced cell cycle arrest ; a phenotype similar to that observed in EFs lacking p53. Furthermore, we showed that transcriptional induction of the gene encoding the cell cycle inhibitor p21 by DNA-damage is dependent on both factors, and that the p21 promoter is activated by both. These studies revealed that p53 and IRF-1 possess both non-overlapping and overlapping functions in different type of cells, and also demonstrates a unique example of two tumor suppressor transcription factors which functionally converge to regulate the cell cyclethrough activation of a common target (s).
In addition, we purified an IRF-1 association molecule which was revealed to be identical to nucleophosmin (NPM), and found that NPM inhibited the transcriptional activity of IRF-1. Moreover, overexpression of NPM in cells resulted in malignant transformation. These results suggest the possible involvement of NPM in inactivation IRF-1-dependent anti-oncogenic surveillance in human cancer development. Less
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[Publications] Tamura, T., Ishihara, M.Lamphier, M., S.Tanaka, N., Oishi, I., Aizawa, S., Matsuyama, T., Mak, T., Taki, S., and Taniguchi, T.: "An IRF-1-dependent pathway of DNA damage-induced apoptosis in mitogen-activated Tlymphocyte." Nature. 376. 596-599 (1995)
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「研究成果報告書概要(欧文)」より
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[Publications] Tanaka, N., Ishihara, M., Lamphier, M.S., Nozawa, H., Matsuyama, T., Mak, T.W., Aizawa, S., Tokino, T., Oren, M., and Taniguchi, T.: "Cooperation of the tumor suppressors IRF-1 and p53 in response to DNA damage." Nature. 382. 816-818 (1996)
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「研究成果報告書概要(欧文)」より
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[Publications] Kondo, T., Minamino, N., Nagamuma-Inoue, T., Matsumoto, M., Taniguchi, T., and Tanaka, N.: "Identification and characterization of nucleophosmin/B23/numatrin which binds the anti-oncogenic transcription factor IRF-1 and manifests oncogenic activity." Oncogene. 15. 1275-1281 (1997)
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[Publications] Tanaka, N., Sato, M., Lamphier, M.S., Nozawa, H., Oda, E., Noguchi, S., Schireiber, R,D., Tsujimoto, Y., and Taniguchi, T.: "Type I interferons are essential mediators of apoptotic death in virally-infected cells." Genes Cells. 3. 29-37 (1998)
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「研究成果報告書概要(欧文)」より
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