title: Reduction of translation rate stabilizes circadian rhythm and reduces the magnitude of phase shift.
abstract: In the intracellular environment, the circadian oscillator is exposed to molecular noise. Nevertheless, cellular rhythms are robust and show almost constant period length for several weeks. To find which molecular processes modulate the stability, we examined the effects of a sublethal dose of inhibitors for processes in the molecular clock. Inhibition of PER1/2 phosphorylation by CKIε/δ led to reduced amplitude and enhancement of damping, suggesting that inhibition of this process destabilized oscillation. In contrast, moderate inhibition of translation led to stabilization of the circadian oscillation. Moreover, inhibition of translation also reduced magnitude of phase shift. These results suggest that some specific molecular processes are crucial for stabilizing the circadian rhythm, and that the molecular clock may be stabilized by optimizing parameters of some crucial processes in the primary negative feedback loop. Moreover, our findings also suggested that rhythm stability is closely associated with phase stability against stimuli.
authors.affiliation: Department of Anatomy and Neurobiology, Kinki University Faculty of Medicine, 377-2 Ohno-Higashi, Osakasayama City, Osaka 589-8511, Japan. Electronic address: masato.nakajima@gmail.com.
authors.forename: Masato
authors.initials: M
authors.lastname: Nakajima
authors.affiliation: Department of Anatomy and Neurobiology, Kinki University Faculty of Medicine, 377-2 Ohno-Higashi, Osakasayama City, Osaka 589-8511, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Koinuma
authors.affiliation: Department of Anatomy and Neurobiology, Kinki University Faculty of Medicine, 377-2 Ohno-Higashi, Osakasayama City, Osaka 589-8511, Japan. Electronic address: shigey@med.kindai.ac.jp.
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Shigeyoshi
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D048149:Casein Kinase 1 epsilon / Q000235:genetics / Q000378:metabolism; D048148:Casein Kinase Idelta / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D057906:Circadian Clocks / Q000235:genetics*; D002940:Circadian Rhythm / Q000235:genetics*; D003513:Cycloheximide / Q000494:pharmacology; D025461:Feedback, Physiological; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D017930:Genes, Reporter; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D056950:Period Circadian Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D010957:Plasmids / Q000737:chemistry / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects*; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection
chemical_list: D000873:Anthracenes; C539023:Per1 protein, mouse; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D011993:Recombinant Fusion Proteins; C432165:pyrazolanthrone; D003513:Cycloheximide; D008156:Luciferases; D048149:Casein Kinase 1 epsilon; D048148:Casein Kinase Idelta; D048670:MAP Kinase Kinase 4
keywords: Circadian clock; Phase shift; Robustness; Stability