Molecular mechanism on the development of type 2 diabetes

• Project/Area Number: 20390058
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General physiology
• Research Institution: Kumamoto University
• Principal Investigator: TOMIZAWA Kazuhito Kumamoto University, 大学院・生命科学研究部, 教授 (40274287)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥19,500,000 (Direct Cost: ¥15,000,000、Indirect Cost: ¥4,500,000); Fiscal Year 2010: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000); Fiscal Year 2009: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000); Fiscal Year 2008: ¥7,280,000 (Direct Cost: ¥5,600,000、Indirect Cost: ¥1,680,000)
• Keywords: 糖尿病 / tRNA / 化学修飾 / インスリン / 遺伝子改変マウス / Cdk5 / 細胞内情報伝達 / 修飾酵素 / リン酸化 / 蛋白質相互作用

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.

Research Products

• [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.
  • Journal Title: Nat.Cell Biol. in press.
• [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.
  • Journal Title: PLoS One 6
  • NAID: 120005232485
• [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., Tomizawa K., et al.
  • Journal Title: Nat.Cell Biol. Volume: 13(印刷中)
  • Peer Reviewed
• [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.
  • Journal Title: J Biol.Chem. 285 Pages: 28425-28433
• [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.
  • Journal Title: Neurosci.Res. 68 Pages: 151-153
• [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.
  • Journal Title: Biomaterials 31 Pages: 4139-4145
• [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.
  • Journal Title: Urology 75 Pages: 813-819
• [Journal Article] Identification of eukaryotic and prokaryotic methythiotransferases for biosynthesis of 2-methylthio-N6-threonylcarbamoyladenosine in tRNA. (2010)
  • Author(s): Arragain S., Tomizawa K., et al.
  • Journal Title: J.Biol.Chem. Volume: 285 Pages: 28425-28433
  • Peer Reviewed
• [Journal Article] Development of a bifunctional immunoliposome system for combined drug delivery and imaging in vivo. (2010)
  • Author(s): Feng B., Tomizawa K., et al.
  • Journal Title: Biomaterials Volume: 31 Pages: 4139-4145
  • Peer Reviewed
• [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.
  • Journal Title: J Control Release 138 Pages: 128-133
  • NAID: 120002723158
• [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.
  • Journal Title: Biomaterials 30 Pages: 1746-1755
• [Journal Article] Effects of purified newly developed botulinum neurotoxin type A in rat prostate (2009)
  • Author(s): Nishiyama Y, Yokoyama T, Tomizawa K, et.al
  • Journal Title: Urology 74 Pages: 436-439
  • Peer Reviewed
• [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., et al.
  • Journal Title: Biomaterials 30 Pages: 1746-1755
  • Peer Reviewed
• [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, et al.
  • Journal Title: J Control Release 138 Pages: 128-133
  • Peer Reviewed
• [Journal Article] Delivery of sodium borocaptate to glioma cells using immunoliposome conjugated with anti-EGFR antibodies by ZZ-His (2009)
  • Author(s): Feng B., et. al
  • Journal Title: Biomaterials 30 Pages: 1746-1755
  • Peer Reviewed
• [Journal Article] CaM kinase 1a-induced phosphorylation of DRP1 regulates mitochondrial morphology (2008)
  • Author(s): Han XJ., et. al
  • Journal Title: J. Cell Biol. 182 Pages: 573-585
  • Peer Reviewed
• [Presentation] ヒトtRNA修飾と疾患 (2010)
  • Author(s): 富澤一仁
  • Organizer: 第12回日本RNA学会年会
  • Place of Presentation: 学術総合センター一ツ橋記念講堂(東京)
  • Year and Date: 2010-07-27
• [Presentation] ヒトtRNA修飾と2型糖尿病発症 (2010)
  • Author(s): 富澤一仁
  • Organizer: 第12回日本RNA学会年会
  • Place of Presentation: 学士会館(東京都)
  • Year and Date: 2010-07-27
• [Presentation] Functional characterization of CDKAL1, a risk factor of T2DM (2010)
  • Author(s): 富澤一仁
  • Organizer: 第53回日本糖尿病学会
  • Place of Presentation: 岡山コンベンションセンター(岡山)
  • Year and Date: 2010-05-28
• [Presentation] Functional characterization of CDKAL1, a risk factor of T2DM. (2010)
  • Author(s): 富澤一仁
  • Organizer: 第53回日本糖尿病学会
  • Place of Presentation: 岡山コンベンションセンター(岡山市)
  • Year and Date: 2010-05-28
• [Presentation] Functional characterization of a novel type 2 diabetes risk factor, Cdk5 regulator subunit association protein 1-like 1 (CDKAL1). (2009)
  • Author(s): Fan-Yan Wei, Kazuhito Tomizawa.
  • Organizer: The 25th Kumamoto Medical Bioscience Symposium
  • Place of Presentation: ANA Hotel Kumamoto New Sky (Kumamoto).
  • Year and Date: 2009-11-12
• [Remarks] ホームページ等
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• [Remarks]
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• [Patent(Industrial Property Rights)] 2型糖尿病モデル非ヒト動物 (2009)
  • Inventor(s): 富澤一仁、魏范研
  • Industrial Property Rights Holder: 熊本大学
  • Filing Date: 2009-11-11
• [Patent(Industrial Property Rights)] 2型糖尿病モデル非ヒト動物 (2009)
  • Inventor(s): 富澤一仁, 魏范研
  • Industrial Property Rights Holder: 熊本大学
  • Industrial Property Number: 2009-258382
  • Filing Date: 2009-11-11