2004 Fiscal Year Final Research Report Summary
Elucidation of the mechanism of TNF-induced reactive oxygen species-dependent cytotoxicity and development of its clinical application
| Project/Area Number |
15390131
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Experimental pathology
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| Research Institution | Juntendo University |
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Principal Investigator |
NAKANO Hiroyasu Juntendo Univ., Dept. Immunology, Assistant professor, 医学部, 講師 (70276476)
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| Project Period (FY) |
2003 – 2004
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| Keywords | TNFα / NF-κB / reactive oxygen species(ROS) / JNK / necrosis / apoptosis / ER stress / oxidative stress |
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| Research Abstract |
By using NF-κB activation-deficient cells, we demonstrate that TNFα stimulation leads to accumulation of reactive oxygen species(ROS), which is essential for prolonged mitogen-activated protein kinase(MAPK) activation and necrotic cell death. Moreover, microarray analysis shows that several antioxidant enzymes are induced by TNFα in an NF-κB-dependent manner. Collectively, a novel function of NF-κB is to suppress TNF-induced ROS accumulation by upregulating anti-oxidant enzymes.
Accumulation of unfolded proteins in the endoplasmic reticulum(ER) causes ER overload, resulting in ER stress. To cope with ER stress, mammalian cells trigger a specific response known as the unfolded protein response(UPR). By using murine fibrosarcoma L929 cells, in which tumor necrosis factor(TNF)α induces accumulation of reactive oxygen species(ROS) and cell death, we show that TNFαTh induces the UPR in a ROS-dependent fashion. In contrast to TNFα, oxidative stresses by H_2O_2 or arsenite only induce eIF2α phosphorylation, but not activation of PERK- or IRE1-dependent pathways, indicating the specificity of downstream signaling induced by various oxidative stresses. Conversely, the UPR induced by tunicamycin substantially suppresses TNFα-induced ROS accumulation and cell death. Collectively, some, but not all, oxidative stresses induce the UPR, and preemptive UPR counteracts TNFα-induced ROS accumulation.
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Research Products
(33 results)
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[Journal Article] Genome wide analysis of TNF-inducible genes reveals that antioxidant enzymes are induced by TNF and responsible for elimination of ROS.2004
Author(s)
Sasazuki, T., T.Okazaki, K.Tada, S.Sakon-Komazawa, M.Katano, M.Tanaka, H.Yagita, K.Okumura, N.Tominaga, Y.Hayashizaki, Y Okazaki, H.Nakano.
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Journal Title
Mol Immunol. 41
Pages: 547-551
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] NT-κB inhibits TNT-induced accumulation of ROS that mediate prolonged MAPK activation and necroti cell death.2004
Author(s)
Sakon, S., X.Xue, M.Takekawa, T.Sasazuki, T.Okazaki, Y Kojima, J.H.Piao, H.Yagita, K.Okumura, T.Doi, H.Nakano.
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Description
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[Journal Article] Epstein-Barr virus latent membrane protein 1 activation of NF-κB through IRAK1 and TRAF6.2003
Author(s)
Luftig, M., B.Prinarakis, T.Yasui, T.Tsichritzis, E.Cahir-McFarland, J.Inoue, H.Nakano, T.W.Mak, W.C.Yeh, X.Li, S.Akira, N.Suzuki, S.Suzuki, G.Mosialos, E.Kieff.
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Journal Title
Proc NatI Acad Sci U S A 100
Pages: 15595-15600
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Tumor Necrosis Factor α-induced IKK Phosphorylation of NF-κB p65 on Serine 536 Is Mediated through the TRAF2, TRAF5, and TAK1 Signaling Pathway.2003
Author(s)
Sakurai, H., S.Suzuki, N.Kawasaki, H.Nakano, T.Okazaki, A.Chino, T.Doi, I.Saiki.
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Journal Title
J Biol Chem 278
Pages: 36916-36923
Description
「研究成果報告書概要(欧文)」より
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