title: Mitomycin C modulates the circadian oscillation of clock gene period 2 expression through attenuating the glucocorticoid signaling in mouse fibroblasts.
abstract: Clock gene regulates the circadian rhythm of various physiological functions. The expression of clock gene has been shown to be attenuated by certain drugs, resulting in a rhythm disorder. Mitomycin C (MMC) is often used in combination with ophthalmic surgery, especially in trabeculectomy, a glaucoma surgical procedure. The purpose of this study was to investigate the influence of MMC on clock gene expression in fibroblasts, the target cells of MMC. Following MMC treatment, Bmal1 mRNA levels was significantly decreased, whereas Dbp, Per1, and Rev-erbα mRNA levels were significantly increased in the mouse fibroblast cell line NIH3T3 cells. Microarray analysis was performed to explore of the gene(s) responsible for MMC-induced alteration of clock gene expression, and identified Nr3c1 gene encoding glucocorticoid receptor (GR) as a candidate. MMC suppressed the induction of Per1 mRNA by dexamethasone (DEX), ligand of GR, in NIH3T3 cells. MMC also modulated the DEX-driven circadian oscillations of Per2::Luciferase bioluminescence in mouse-derived ocular fibroblasts. Our results demonstrate a previously unknown effect of MMC in GR signaling and the circadian clock system. The present findings suggest that MMC combined with trabeculectomy could increase the risk for a local circadian rhythm-disorder at the ocular surface.
authors.affiliation: Department of Ophthalmology, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, Yufu-shi, Oita 879-5593, Japan. Electronic address: naoki-0207@umin.ac.jp.
authors.forename: Naoki
authors.initials: N
authors.lastname: Kusunose
authors.affiliation: Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Matsunaga
authors.affiliation: Department of Ophthalmology, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, Yufu-shi, Oita 879-5593, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Kimoto
authors.affiliation: Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Akamine
authors.affiliation: Drug Innovation Research Center, Daiichi University of Pharmacy, 22-1 Tamagawa-cho, Minami-ku, Fukuoka 815-8511, Japan.
authors.forename: Kengo
authors.initials: K
authors.lastname: Hamamura
authors.affiliation: Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Koyanagi
authors.affiliation: Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Shigehiro
authors.initials: S
authors.lastname: Ohdo
authors.affiliation: Department of Ophthalmology, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, Yufu-shi, Oita 879-5593, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Kubota
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics; D000818:Animals; D056926:CLOCK Proteins / Q000235:genetics*; D021081:Chronobiology Disorders / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D057906:Circadian Clocks / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D002940:Circadian Rhythm / Q000187:drug effects* / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology; D005123:Eye / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D016685:Mitomycin / Q000009:adverse effects / Q000494:pharmacology*; D041681:NIH 3T3 Cells; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 / Q000235:genetics; D056950:Period Circadian Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D014130:Trabeculectomy / Q000009:adverse effects; D014157:Transcription Factors / Q000235:genetics
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; D004268:DNA-Binding Proteins; C498260:Dbp protein, mouse; C575863:NR3C1 protein, mouse; C498262:Nr1d1 protein, mouse; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; C539023:Per1 protein, mouse; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D014157:Transcription Factors; D016685:Mitomycin; D003907:Dexamethasone; D056926:CLOCK Proteins; C538944:Clock protein, mouse
keywords: Circadian rhythm; Clock gene; Glucocorticoid receptor; Mitomycin C; Trabeculectomy