2018 Fiscal Year Final Research Report
Elucidating the molecular mechanism by which tumor suppressor Notch1 is inactivated by xylosyl-extension
| Project/Area Number |
17H06743
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| Research Category |
Grant-in-Aid for Research Activity Start-up
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| Allocation Type | Single-year Grants |
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| Research Field |
Functional biochemistry
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| Research Institution | Nagoya University |
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Principal Investigator |
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| Research Collaborator |
URATA yusuke
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| Project Period (FY) |
2017-08-25 – 2019-03-31
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| Keywords | O-グルコース糖鎖 / Notch1 / Notch シグナル / 糖転移酵素 / キシロース / 腫瘍抑制因子 |
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| Outline of Final Research Achievements |
The PI hypothesized that carcinogenesis and elevated proliferation of AML and squamous carcinoma are caused by aberrantly increased xylosylation of O-glucose glycans on Notch1. Here, as an initial step of our long-term research, we examined the structures of O-glucose glycans on Notch1 and whether it is possible to manipulate the extent of xylosyl-extension of O-glucose glycans on Notch1 by genetically engineering the genes that encode the xylosyltransferases. We accomplished the comprehensive analysis of O-glucose glycans on Notch1 produced in cultured cell lines. Furthermore, as expected, knocking out of XXYLT1 resulted in loss of the addition of the terminal xylose residues at a non-reducing end of O-glucose glycans on Notch1, and knocking out both GXYLT1 and GXYLT2 resulted in loss of xylosyl-extension of O-glucose glycans on Notch1.
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| Free Research Field |
Glycobiology
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| Academic Significance and Societal Importance of the Research Achievements |
O-グルコース糖鎖キシロース伸長は、Notch1の小胞体内品質管理と、細胞表面におけるリガンド結合に寄与している可能性がある。Notch1 上の O-グルコース糖鎖修飾プロファイルは、これまでに報告がなかったが、本研究により、初めてそれが明らかとなった。現段階では培養細胞由来の解析結果であり、今後、生体試料でも同様の解析をしていく必要がある。そして、それらの情報を活用することにより、Notch1 受容体を介したシグナル伝達機構の制御に関する分子メカニズムの解明と、Notch シグナルの異常に起因する病態の診断および治療法の開発に資することが期待される。
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