title: A molecular clock regulates angiopoietin-like protein 2 expression.
abstract: Various physiological and behavioral processes exhibit circadian rhythmicity. These rhythms are usually maintained by negative feedback loops of core clock genes, namely, CLOCK, BMAL, PER, and CRY. Recently, dysfunction in the circadian clock has been recognized as an important foundation for the pathophysiology of lifestyle-related diseases, such as obesity, cardiovascular disease, and some cancers. We have reported that angiopoietin-like protein 2 (ANGPTL2) contributes to the pathogenesis of these lifestyle-related diseases by inducing chronic inflammation. However, molecular mechanisms underlying regulation of ANGPTL2 expression are poorly understood. Here, we assess circadian rhythmicity of ANGPTL2 expression in various mouse tissues. We observed that ANGPTL2 rhythmicity was similar to that of the PER2 gene, which is regulated by the CLOCK/BMAL1 complex. Promoter activity of the human ANGPTL2 gene was significantly induced by CLOCK and BMAL1, an induction markedly attenuated by CRY co-expression. We also identified functional E-boxes in the ANGPTL2 promoter and observed occupancy of these sites by endogenous CLOCK in human osteosarcoma cells. Furthermore, Cry-deficient mice exhibited arrhythmic Angptl2 expression. Taken together, these data suggest that periodic expression of ANGPTL2 is regulated by a molecular clock.
authors.affiliation: Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. tkado@gpo.kumamoto-u.ac.jp
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Kadomatsu
authors.forename: Shota
authors.initials: S
authors.lastname: Uragami
authors.forename: Makoto
authors.initials: M
authors.lastname: Akashi
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Tsuchiya
authors.forename: Hiroo
authors.initials: H
authors.lastname: Nakajima
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Nakashima
authors.forename: Motoyoshi
authors.initials: M
authors.lastname: Endo
authors.forename: Keishi
authors.initials: K
authors.lastname: Miyata
authors.forename: Kazutoyo
authors.initials: K
authors.lastname: Terada
authors.forename: Takeshi
authors.initials: T
authors.lastname: Todo
authors.forename: Koichi
authors.initials: K
authors.lastname: Node
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Oike
mesh_terms: D056930:ARNTL Transcription Factors / Q000378:metabolism; D000091302:Angiopoietin-Like Protein 2; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D056926:CLOCK Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D057906:Circadian Clocks; D002940:Circadian Rhythm; D056931:Cryptochromes / Q000378:metabolism; D024721:E-Box Elements / Q000235:genetics; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: C485792:ANGPTL2 protein, human; D056930:ARNTL Transcription Factors; D000091302:Angiopoietin-Like Protein 2; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; C485793:Angptl2 protein, mouse; D056931:Cryptochromes; D012333:RNA, Messenger; D056926:CLOCK Proteins