2010 Fiscal Year Final Research Report
Molecular mechanism on the development of type 2 diabetes
| Project/Area Number |
20390058
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General physiology
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| Research Institution | Kumamoto University |
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Principal Investigator |
TOMIZAWA Kazuhito Kumamoto University, 大学院・生命科学研究部, 教授 (40274287)
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| Project Period (FY) |
2008 – 2010
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| Keywords | 糖尿病 / tRNA / 化学修飾 / インスリン / 遺伝子改変マウス |
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| Research Abstract |
Cdkal1 has been associated with an impaired insulin response and increased risk of type 2 diabetes (T2D), but its molecular function has not been characterized. Here, we show that Cdkal1 is a mammalian methylthiotransferase that biosynthesizes 2-methylthio-N^6- threonylcarbamoyladenosine (ms^2t^6A) in tRNA^<Lys>(UUU) and that it is required for the accurate translation of AAA and AAG codons. Pancreatic?-cell-specific Cdkal1 knockout mice showed pancreatic islet hypertrophy, a decrease in insulin secretion and impaired blood glucose control. In Cdkal1-deficient?-cells, glucose-stimulated proinsulin synthesis was reduced. Moreover, the expression of endoplasmic reticulum (ER) stress-related genes was upregulated in these cells, and abnormally structured ER was observed. Cdkal1 knockout mice were hypersensitive to high-fat diet-induced ER stress. These findings suggest that the induced translation of proinsulin may require fully modified tRNA^<Lys>(UUU), potentially explaining the molecular pathogenesis of T2D in patients carrying cdkal1 risk alleles.
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[Journal Article] Ciliary transition zone activation of phospho-Tctex-1 controls ciliary resorption, S-phase entry and fate of neural progenitors.2011
Author(s)
Li, A., Saito, M., Chuang, J.-Z., Tseng, Y.-Y., Dedesma, C., Tomizawa, K., Kaitsuka, T., Sung, C.-H.
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Journal Title
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[Journal Article] Expression of a constitutively active calcineurin encoded by an intron-retaining mRNA in follicular keratinocytes.2011
Author(s)
Fujimura, A., Michiue, H., Nishiki, T.Ohmori, I., Wei, F.-Y., Matsui, H., Tomizawa, K.
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Journal Title
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[Journal Article] Identification of eukaryotic and prokaryotic methythiotransferases for biosynthesis of 2-methylthio-N6-reonylcarbamoyladenosine in tRNA.2010
Author(s)
Arragain, S., Handelman, S.K., Forouhar, F., Wei, F.-Y., Tomizawa, K., Hunt, J.F., Douki, T., Fontecave M., Mulliez, E, Atta, M.
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Journal Title
J Biol.Chem. 285
Pages: 28425-28433
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[Journal Article] Oxytocin mediates the antidepressant effects of mating behavior in male mice.2010
Author(s)
Matsushita, M., Tomizawa, K., Okimoto, N., Nishiki, T., Ohmori, I., Matsui, H.
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Journal Title
Neurosci.Res. 68
Pages: 151-153
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[Journal Article] Development of a bifunctional immunoliposome system for combined drug delivery and imaging in vivo.2010
Author(s)
Feng, B., Tomizawa, K., Michiue, H., Han, X.-H., Miyatake, S., Matsui, H.
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Journal Title
Biomaterials 31
Pages: 4139-4145
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[Journal Article] Cell-penetrating D-isomer peptides of p53 C-terminus: Long-term inhibitory effect on the growth of bladder cancer.2010
Author(s)
Araki, D., Takayama, K., Inoue, M., Watanabe, T., Kumon, H., Futaki, S., Matsui, H., Tomizawa, K.
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Journal Title
Urology 75
Pages: 813-819
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[Journal Article] Enhanced intracellular delivery using arginine-rich peptides by the addition of penetration accelerating sequences (Pas).2009
Author(s)
Takayama, K., Nakase, I., Michiue, H., Takeuchi, T., Tomizawa, K., Matsui, H., Futaki, S.
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Journal Title
J Control Release 138
Pages: 128-133
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[Journal Article] Delivery of sodium borocaptate to glioma cells using immunoliposome conjugated with anti-EGFR antibodies by ZZ-His.2009
Author(s)
Feng, B., Tomizawa, K., Michiue, H., Miyatake, S., Han, X.-H., Fujimura, A., Seno, M., Kirihata, M., Matsui, H.
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Journal Title
Biomaterials 30
Pages: 1746-1755
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