Nuclear entry of the circadian regulator mPER1 is controlled by mammalian casein kinase I epsilon

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E Vielhaber1, E Eide, A Rivers

  • 1Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City 84132, USA.

Molecular and Cellular Biology
|June 10, 2000
PubMed

Insights

Mammalian casein kinase I epsilon (CKIepsilon) regulates circadian rhythms by controlling the nuclear entry of the mPER1 protein. This phosphorylation-dependent process involves interactions with mPER2, impacting the molecular oscillator.

Area of Science:

  • Molecular Biology
  • Chronobiology
  • Genetics

Background:

  • Circadian time is regulated by a molecular oscillator driven by negative feedback loops.
  • Nuclear entry of circadian regulatory proteins is crucial for this loop in both flies and mammals.
  • The Drosophila double-time gene product, a casein kinase I epsilon (CKIepsilon) homolog, interacts with dPER to regulate circadian cycle length.

Purpose of the Study:

  • To investigate the interaction between mammalian casein kinase I epsilon (CKIepsilon) and the murine circadian regulator mPER1.
  • To elucidate the mechanisms regulating mPER1 nuclear entry and its role in the mammalian circadian clock.

Main Methods:

  • HEK 293 cells were used to study protein interactions and localization.
  • Coexpression of mPER1 with mPER2 and CKIepsilon was analyzed.
  • Phosphorylation-dependent cytoplasmic retention and nuclear localization signals were investigated.

Main Results:

  • Mammalian CKIepsilon binds to and phosphorylates mPER1.
  • Unlike dPER and mPER2, mPER1 is predominantly nuclear when expressed alone.
  • mPER1 nuclear entry is retarded by heterodimerization with mPER2 and by CKIepsilon-mediated phosphorylation and cytoplasmic retention.

Conclusions:

  • CKIepsilon plays a critical role in the mammalian circadian clock by regulating mPER1 nuclear entry.
  • mPER1 nuclear localization is modulated by interactions with mPER2 and CKIepsilon.
  • Phosphorylation by CKIepsilon leads to cytoplasmic retention of mPER1, influencing circadian rhythm.

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