title: Lycorine, a candidate for the control of period length in mammalian cells.
abstract: Plants of the Amaryllidaceae family have been used as therapeutic agents against CNS related maladies such as Alzheimer's disease. The known primary alkaloid constituents have significant biological activity. We identified the Lycoris alkaloids lycorine and lycoricidinol from Amaryllidaceae using a real-time reporter gene assay system based on NIH3T3 cells. These alkaloids have a wide spectrum of pharmacological actions and dose-dependently lengthen the circadian period. When cells that had been incubated with lycorine or lycoricidinol were washed and then incubated without these alkaloids, period length reverted to that of control cells, suggesting that elongation of the circadian period induced by lycorine and lycoricidinol is reversible. Although one of its major activities is the inhibition of protein synthesis, lycorine induced dose-dependent period elongation regardless of the presence of cycloheximide and moreover, cycloheximide, itself did not affect period length, suggesting that lycorine dose-dependently extends the circadian period by a mechanism other than translational inhibition. Real-time RT-PCR showed that lycorine enhanced RORα and Bmal1 transcription, and exogenous expression and knockdown of Bmal1 also caused long and short periods, respectively, thus confirming the phenotype indicated by lycorine. These data indicate that lycorine and lycoricidinol modulate Bmal1 transcription and the circadian period, and also suggest that Lycoris alkaloids are novel contributors to the control of period length in mammalian cells.
authors.affiliation: Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology, Higashi, Tsukuba, Japan. y-onishi@aist.go.jp
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Onishi
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kawano
authors.forename: Yoshimitsu
authors.initials: Y
authors.lastname: Yamazaki
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics / Q000378:metabolism*; D047151:Amaryllidaceae Alkaloids / Q000494:pharmacology*; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D002940:Circadian Rhythm / Q000187:drug effects*; D003513:Cycloheximide / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D017930:Genes, Reporter; D031426:Lycoris / Q000737:chemistry; D008322:Mammals; D051379:Mice; D041681:NIH 3T3 Cells; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000235:genetics / Q000378:metabolism; D010617:Phenanthridines / Q000494:pharmacology*; D010766:Phosphorylation; D010957:Plasmids / Q000235:genetics / Q000378:metabolism; D014176:Protein Biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: D056930:ARNTL Transcription Factors; D047151:Amaryllidaceae Alkaloids; C538961:Bmal1 protein, mouse; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D010617:Phenanthridines; C539739:Rora protein, mouse; C423646:lycoricidinol; D003513:Cycloheximide; C015330:lycorine