Timeless is an important mediator of Ck2 effects on circadian clock function in vivo

Rose Anne Meissner, Valerie L. Kilman, Jui Ming Lin, Ravi Allada*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

Circadian oscillations in clock components are central to generation of self-sustained 24-h periodicity. In the Drosophila molecular clock, accumulation, phosphorylation, and degradation of PERIOD (PER) and TIMELESS (TIM) proteins govern period length. Yet little is known about the kinases that phosphorylate TIM in vivo. It has been shown previously that the protein kinase CK2 phosphorylates TIM in vitro. Here, we identify a role for CK2 in TIM regulation in vivo. Induction of a dominant-negative CK2α, CK2αTik (Tik), increases TIM protein and tim transcript levels, reduces oscillation amplitude, and results in persistent cytoplasmic TIM localization. Exposure to light and subsequent TIM degradation results in an increase in the fraction of the transcriptional repressor PER that is nuclear and suppression of per and tim RNA levels. TIM protein, but not tim transcript, levels are elevated in Tik mutants in a per01 background. In contrast, Tik effects on PER are undetectable in a tim01 background, suggesting that TIM is required for CK2 effects on PER. To identify potential CK2 target sites, we assayed TIM phosphorylation rhythms in a deletion mutant that removes a conserved serine-rich domain and found that TIM protein does not show robust rhythmic changes in mobility by Western blotting, a hallmark of rhythmic phosphorylation. The period lengthening effects in Tik heterozygotes are reduced in a timUL mutant that disrupts a putative CK2 phosphorylation site. Together, these data indicate that TIM is an important mediator of CK2 effects on circadian rhythms.

Original languageEnglish (US)
Pages (from-to)9732-9740
Number of pages9
JournalJournal of Neuroscience
Volume28
Issue number39
DOIs
StatePublished - Sep 24 2008

Keywords

  • CK2
  • Circadian
  • Drosophila
  • Period
  • Phosphorylation
  • Timeless

ASJC Scopus subject areas

  • Neuroscience(all)

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