Multiple signaling pathways elicit circadian gene expression in cultured Rat-1 fibroblasts

Curr Biol. 2000 Oct 19;10(20):1291-4. doi: 10.1016/s0960-9822(00)00758-2.


In mammals, all overt circadian rhythms are thought to be coordinated by a central pacemaker residing in the hypothalamic suprachiasmatic nucleus (SCN) [1]. The phase of this pacemaker is entrained by photic cues via the retino-hypothalamic tract. Circadian clocks probably rely on a feedback loop in the expression of certain clock genes (reviewed in [2,3]). Surprisingly, however, such molecular oscillators are not only operative in pacemaker cells, such as SCN neurons, but also in many peripheral tissues and even in cell lines kept in vitro [4-7]. For example, a serum shock can induce circadian gene expression in cultured Rat-1 fibroblasts [5]. This treatment also results in a rapid surge of expression of the clock genes Per1 and Per2, similar to that observed in the SCNs of animals receiving a light pulse [8-10]. Serum induction of Per1 and Per2 transcription does not require ongoing protein synthesis [5] and must therefore be accomplished by direct signaling pathways. Here, we show that cAMP, protein kinase C, glucocorticoid hormones and Ca2+ can all trigger a transient surge of Per1 transcription and elicit rhythmic gene expression in Rat-1 cells. We thus suspect that the SCN pacemaker may exploit multiple chemical cues to synchronize peripheral oscillators in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biological Clocks
  • Bucladesine / pharmacology
  • Calcimycin / pharmacology
  • Cell Cycle Proteins
  • Cell Line
  • Circadian Rhythm / genetics*
  • Colforsin / pharmacology
  • Culture Media
  • Dimethyl Sulfoxide / pharmacology
  • Epidermal Growth Factor / pharmacology
  • Fibroblasts / physiology
  • Gene Expression Regulation* / drug effects
  • Insulin / pharmacology
  • Nuclear Proteins / genetics*
  • Okadaic Acid / pharmacology
  • Period Circadian Proteins
  • Rats
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Tetradecanoylphorbol Acetate / pharmacology
  • Transcription Factors
  • Transcription, Genetic / drug effects


  • Cell Cycle Proteins
  • Culture Media
  • Insulin
  • Nuclear Proteins
  • Per1 protein, mouse
  • Per1 protein, rat
  • Per2 protein, mouse
  • Per2 protein, rat
  • Period Circadian Proteins
  • Transcription Factors
  • Colforsin
  • Okadaic Acid
  • Calcimycin
  • Epidermal Growth Factor
  • Bucladesine
  • Tetradecanoylphorbol Acetate
  • Dimethyl Sulfoxide