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: Naoki Kusunose, Naoya Matsunaga, Kenichi Kimoto, Takahiro Akamine, Kengo Hamamura, Satoru Koyanagi, Shigehiro Ohdo, Toshiaki Kubota
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 467 Issue 1 Pg. 157-63 (Nov 06 2015) ISSN: 1090-2104 [Electronic] United States
• PMID: 26403971 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• ARNTL Transcription Factors
• Arntl protein, mouse
• DNA-Binding Proteins
• Dbp protein, mouse
• NR3C1 protein, mouse
• Nr1d1 protein, mouse
• Nuclear Receptor Subfamily 1, Group D, Member 1
• Per1 protein, mouse
• Per2 protein, mouse
• Period Circadian Proteins
• RNA, Messenger
• Receptors, Glucocorticoid
• Transcription Factors
• Mitomycin
• Dexamethasone
• CLOCK Proteins
• Clock protein, mouse

Topics

• ARNTL Transcription Factors (genetics)
• Animals
• CLOCK Proteins (genetics)
• Chronobiology Disorders (etiology, genetics, metabolism)
• Circadian Clocks (drug effects, genetics, physiology)
• Circadian Rhythm (drug effects, genetics)
• DNA-Binding Proteins (genetics)
• Dexamethasone (pharmacology)
• Eye (metabolism)
• Gene Expression (drug effects)
• Mice
• Mice, Transgenic
• Mitomycin (adverse effects, pharmacology)
• NIH 3T3 Cells
• Nuclear Receptor Subfamily 1, Group D, Member 1 (genetics)
• Period Circadian Proteins (genetics)
• RNA, Messenger (genetics, metabolism)
• Receptors, Glucocorticoid (genetics)
• Signal Transduction (drug effects)
• Trabeculectomy (adverse effects)
• Transcription Factors (genetics)