title: Bidirectional CLOCK/BMAL1-dependent circadian gene regulation by retinoic acid in vitro.
abstract: A central circadian clock located in the suprachiasmatic nucleus (SCN) of the mammalian hypothalamus entrains peripheral clocks through both neural and humoral factors. Although candidates for entrainment factors have been described, their details remain obscure. Here, we screened ligands for nuclear receptors that affect CLOCK/BMAL1-dependent transactivation of the mouse Period1 (mPer1) gene in NIH3T3 cells. We found that retinoic acids (RAs) significantly up-regulate mPer1 expression in an E-box-dependent manner. We also found that RAs up-regulate the expression of other E-box-dependent circadian genes such as mPer2, arginine vasopressin (mAVP), and peroxisome proliferator-activated receptor alpha (mPPARalpha). Surprisingly, the effect of RAs on CLOCK/BMAL1 (E-box)-dependent mRNA expression was bidirectional and depended on the presence of exogenous retinoic acid receptor alpha (RARalpha). These results suggest that RAs regulate the CLOCK/BMAL1-dependent transcription of circadian genes in a complex manner.
authors.affiliation: Clock Cell Biology Research Group, Institute for Biological Resources and Functions, National Institute of Advanced Industrial Science and Technology, Central 6, 1-1-1 Higashi, Tsukuba, Ibaraki 305-8566, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Shirai
authors.forename: Katsutaka
authors.initials: K
authors.lastname: Oishi
authors.forename: Norio
authors.initials: N
authors.lastname: Ishida
mesh_terms: D056930:ARNTL Transcription Factors; D000818:Animals; D001127:Arginine Vasopressin / Q000096:biosynthesis; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D056926:CLOCK Proteins; D018797:Cell Cycle Proteins / Q000096:biosynthesis; D002940:Circadian Rhythm / Q000502:physiology*; D024721:E-Box Elements / Q000502:physiology; D005136:Eye Proteins / Q000096:biosynthesis; D051379:Mice; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000096:biosynthesis; D047493:PPAR alpha / Q000096:biosynthesis; D056950:Period Circadian Proteins; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000096:biosynthesis; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology / Q000502:physiology*; D015854:Up-Regulation
chemical_list: D056930:ARNTL Transcription Factors; D001127:Arginine Vasopressin; D051792:Basic Helix-Loop-Helix Proteins; D056926:CLOCK Proteins; D018797:Cell Cycle Proteins; D005136:Eye Proteins; D009687:Nuclear Proteins; D047493:PPAR alpha; D056950:Period Circadian Proteins; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D015534:Trans-Activators; D014157:Transcription Factors; D014212:Tretinoin; C538961:Bmal1 protein, mouse; C539023:Per1 protein, mouse; C513312:Per2 protein, mouse; C000607072:Rara protein, mouse; C538944:Clock protein, mouse