| Budget Amount *help |
¥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)
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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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