2011 Fiscal Year Final Research Report
Characterization of Cdkal1, a novel type 2 diabetes risk gene
| Project/Area Number |
22790214
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
General physiology
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| Research Institution | Kumamoto University |
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Principal Investigator |
WEI Fanyan 熊本大学, 大学院・生命科学研究部, 助教 (90555773)
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| Project Period (FY) |
2010 – 2011
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| Keywords | 病態生理 / 糖尿病 |
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| Research Abstract |
Genetic variations in cdkal1(Cdk5 regulatory subunit associated protein 1-like 1) have been identified as a risk for type 2 diabetes. Despite the accumulating clinical evidence, the molecular characterization of Cdkal1 is completely unknown. To investigate the physiological role of Cdkal1, pancreatic b-cell-specific Cdkal1 knockout(Cdkal1 KO) mice were generated. Cdkal1 KO mice showed glucose intolerance and impaired insulin secretion. We have identified that Cdkal1 is a mammalian methylthiotranferase, which specifically modifies tRNA^<Lys>(UUU) at position 37 by catalyzing the biosynthesis of N6-threonylcabamoyladenosine(t6A) to 2-methylthio-N6-threonylcabamoyladenosine(ms2t6A) in both bacteria and mammalian cells. Modification of tRNA^<Lys>(UUU) by Cdkal1 is critical for the accurate decoding of Lys codon. In Cdkal1 KO b-cells, deficiency of modification in tRNA^<Lys>(UUU) caused mistranslation of proinsulin and thus triggered endoplasmic reticulum(ER) stress response. Furthermore, Cdkal1 KO mice fed with a high fat diet developed severe glucose intolerance and ER stress response. From these results, we concluded that modification of tRNA by Cdkal1 in b-cells is critical to maintaining translation fidelity, which contributes to the homeostasis of b-cells.
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[Journal Article] Deficit of Lys-tRNA modification by Cdkal1 causes the development of type 2 diabetes in mice2011
Author(s)
Wei FY, Suzuki T, Watanabe S, Kimura S, Kaitsuka T, Fujimura A, Matsui H, Atta M, Michiue H, Fontecave M, Yamagata K, Suzuki T, Tomizawa K
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Journal Title
J. Clin. Invest
Volume: 121(9)
Pages: 3598-608
Peer Reviewed
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