Molecular mechanism of CHOP dependent cell death induced by extracellular stresses
| Project/Area Number |
16590057
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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 |
Biological pharmacy
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| Research Institution | Nagoya City University |
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Principal Investigator |
HAYASHI Hidetoshi Nagoya City Univ., Grad.Sch.Pharm.Sci., Assoc.Prof., 大学院・薬学研究科, 助教授 (80198853)
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| Co-Investigator(Kenkyū-buntansha) |
ONOZAKI Kikuo Nagoya City Univ., Grad.Sch.Pharm.Sci., Professor, 大学院・薬学研究科, 教授 (20101313)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2005: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 2004: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Keywords | TRB3 / CHOP / ATF4 / p300 / endoplasmic reticulum stress / apoptosis / diabetes / neurodegenerative diseases / ネガティブ・フィードバック / Akt |
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| Research Abstract |
The endoplasmic reticulum(ER) stress is induced by the accumulation of misfolding or malfolding proteins in ER caused by genetic mutation or abnormal modification of proteins. Recently, it is clarified that the ER stress-induced apoptosis cause the neurodegenerative diseases and the diabetes. Applicants are advancing the study of analysis on transcription factor CHOP to which are induced at the ER stress, and are related of apoptosis. Here we have shown that the TRB3, one of the human homologs of a Drosophila kinase like molecule Tribbles, is induced by ER stress and its promoter is activated via ER stress-induced transcription factors, CHOP and ATF4. TRB3 proteins suppress the transcriptional activities of CHOP and ATF4, suggesting CHOP(probably also ATF4)signaling is strictly regulated by TRB3 via a negative feedback mechanism.
In addition, overexpression of TRB3 enhances the ER stress-induced cell death, while the knockdown of TRB3 by a siRNA method decreased the cell death. We have
… More
also observed the association between TRB3 and CHOP by the immunoprecipitaion-Western blot methods. Inhibitory effect of TRB3 on the transcriptional activity of CHOP is Independent of protein degradation. Moreover, the expression of TRB3 did not influence the dimer formation and DNA binding activities of CHOP. However, TRB3 associated with CHOP through its transcriptional domain and this domain is overlapped with a p300 binding domain. Overexpression of TRB3 remarkably inhibited the formation of p300-CHOP complex. These results suggest that TRB3 may function as an antagonist to replace the p300 from CHOP, and control its transcriptional effect. Moreover, transactivational activity of ATF4 is also suppressed by TRB3 probably by the decrease in its stability and by the dissociation of p300 from ATF4.
It is well known that some products necessary for cell survival are the downstream targets of ATF4, suggesting that the downregulation of ATF4 by TRB3 may greatly contribute the apoptosis according to the ER stress. Less
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Report
(3 results)
Research Products
(18 results)
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[Journal Article] Transcriptional induction of Smurf2 ubiquitin ligase by TGF-beta.2005
Author(s)
N.Ohashi, T.Yamamoto, C.Uchida, A.Togawa, H.Fukasawa, Y.Fujigaki, S.Suzuki, K.Kitagawa, T.Hattori, T.Oda, H.Hayashi, A.Hishida, M.Kitagawa
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Journal Title
FEBS Letters 579(12)
Pages: 2557-2563
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