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研究発表を行った学会；
・第３３回日本分子生物学会年会　
　２０１０年１２月７日〜１０日（神戸）

タイトル；Clock genes directly regulate the rhythmic Angptl2 expression.
　
発表者；　門松 毅　氏
　　　（熊本大学　大学院生命科学研究部　分子遺伝学分野）

Abstract；
　Various physiological and behavioral processes exhibit circadian rhythmicity. These rhythms are regulated by a circadian clock system composed of negative feedback loops involving a set of core clock genes. Recent studies have suggested that dysfunction of circadian clock system is involved in the development of obesity and metabolic syndrome. We have recently reported that angiopoietin-like protein 2 (Angptl2) is a key adipocyte-derived inflammatory mediator that links obesity to systemic insulin resistance. However, it is unknown whether clock genes are involved in the regulation of Angptl2 expression. We found that Angptl2 expression clearly shows 24-h rhythmicity in various mouse tissues. This finding suggests that Angptl2 expression is regulated by clock genes. Co-transfection with the human Angptl2 reporter plasmids and the expression plasmids encoding Clock and BMAL1, which are core clock genes and activate the transcription of clock-controlled genes, into HEK293 cells resulted in significantly increased Angptl2 reporter activity. On the other hand, co-transfection with cryptochrome (Cry), which inhibits the activity of Clock/BMAL1 complex, resulted in the suppression of Clock/BMAL1-induced Angptl2 reporter activity. Furthermore, we identified two functional E/E’-box motifs, which is a binding site of the Clock/BMAL1 complex, in the human Angptl2 promoter region. The activity of Angptl2 reporters containing mutations in the E/E’-box motifs significantly decreased compared with that of wild-type Angptl2 reporter. Taken together, these results indicate that clock genes directly regulate the Angptl2 expression and generate its expression rhythmicity.