2017 Fiscal Year Research-status Report
An investigation into the mechanism regulating the oxidative stress-dependent activation of the Keap1-Nrf2 pathway
| Project/Area Number |
16K19027
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| Research Institution | Tohoku University |
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Principal Investigator |
Baird Liam 東北大学, 医学系研究科, 助教 (90724914)
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Keywords | Keap1-Nrf2 |
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| Outline of Annual Research Achievements |
The main aim of this project was to develop a new mouse model in which to study the mechanism of Keap1-dependent regulation of the transcription factor Nrf2. To achieve this aim, we developed a new Nrf2 Dual-ETGE transgenic mouse in which to study the oxidative stress response in vivo. Through analysis of these mice, we found that the replacement of the DLG motif in Nrf2 with an additional ETGE motif did not inhibit the chemical induced activation of Nrf2. In addition, we assayed the stoichiometry of the Nrf2-Keap1-Cul3 complex, and found that this complex is not dissociated by chemical inducers of Nrf2. This suggests that the Nrf2-Keap1-Cul3 complex is inactivated by inducers, but that this activation is not caused by the dissociation of the Keap1 complex upon chemical activation of Nrf2.
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| Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
As we have already made and analysed the Dual-ETGE transgenic mice, we are now able to take the next step in the project by generating structural data to study the mechanism of Keap1 inactivation by chemical inducers.
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| Strategy for Future Research Activity |
Over the final year of the project, we will continue to develop and utilize new structural biology techniques in order to gain a deep and fresh insight into the molecular mechanism of the Keap1-dependent regulation of Nrf2.
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| Causes of Carryover |
The money used last year was for research materials and to attend a conference. For the next fiscal year, the money will be used for research materials.
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[Journal Article] Hyperactivation of Nrf2 in early tubular development induces nephrogenic diabetes insipidus2017
Author(s)
Suzuki T, Seki S, Hiramoto K, Naganuma E, Kobayashi EH, Yamaoka A, Baird L, Takahashi N, Sato H, Yamamoto M.
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Journal Title
Nature Communications
Volume: 8
Pages: 1,13
DOI
Peer Reviewed / Open Access / Int'l Joint Research
