2015 Fiscal Year Final Research Report
Phosphorylation of p62/Sqstm1 activates Nrf2 during selective autophagy
| Project/Area Number |
25460400
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Pathological medical chemistry
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| Research Institution | Niigata University (2015)
Tokyo Metropolitan Institute of Medical Science (2013-2014) |
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Principal Investigator |
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| Co-Investigator(Renkei-kenkyūsha) |
KOMATSU Masaaki 新潟大学, 医歯学系, 教授 (90356254)
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| Project Period (FY) |
2013-04-01 – 2016-03-31
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| Keywords | 選択的オートファジー / p62/Sqstm1 / Keap1-Nrf2システム / リン酸化 / がん |
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| Outline of Final Research Achievements |
In this study, we showed that Ser351 phosphorylation of p62 markedly increases p62’s binding affinity for Keap1, an adaptor of the Cul3 based E3 ubiquitin ligase complex for Nrf2 degradation. Therefore, p62 phosphorylation induces expression of cytoprotective Nrf2 target genes. Importantly, persistent phosphorylation of p62 was observed in hepatic adenoma in autophagy-deficient livers and in several cases of human hepatocellular carcinoma (HCC). Knockout of p62 gene in an HCC cell line markedly abrogated the growth, whereas forced expression of a phosphorylation mimic p62, but not a phosphorylation defective mutant, resulted in recovery of the growth defect. These results indicated the involvement of persistent activation of Nrf2 through the phosphorylation of p62 in hepatoma development.
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| Free Research Field |
生化学、分子生物学
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