2006 Fiscal Year Final Research Report Summary
Stress sensing and protein degradation mechanism of oxidative stress sensor Keapl
| Project/Area Number |
17590238
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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 |
General medical chemistry
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| Research Institution | Tohoku University (2006)
University of Tsukuba (2005) |
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Principal Investigator |
KOBAYASHI Akira Tohoku university, Graduate School of Medicine, Lecture, 大学院医学系研究科, 講師 (50292214)
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| Project Period (FY) |
2005 – 2006
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| Keywords | stress response / oxidative stress / protein degradation / ubiquitin |
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| Research Abstract |
Transcription factor Nrf2 is a major regulator of genes encoding phase 2 detoxifying enzymes and
anti-oxidant stress proteins in response to electrophilic agents and oxidative stress. In the absence of such
stimuli, Nrf2 is inactive owing to its cytoplasmic retention by Keap 1 and rapid degradation through the
proteasome system. In this research, we identified that Nrf2 associates with Keap 1 homodimer complex
through the DLG and ETGE motifs in the two site molecular recognition manner. It seems that this
association allows for the efficient ubiquitin transfer to lysine residues of Nrf2, ultimately resulting in the
rapid degradation of Nrf2 under unstressed conditions. Biochemical study showed that association of
DLG motif with Keapl is weaker that that of ETGE motif. Therefore we hypothesize that oxidative stress
provokes the conformational change of Keapl, resulting in disruption of the weak binding between DLG
and Keap1. This disruption might stabilize and activate Nrf2 because of the inhibited ubiquitination.
This stabilization of Nrf2 by oxidative stress seems to be one of the nature way of stress-mediated
activation of Nrf2.
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