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High-throughput chemical screen identifies a novel potent modulator of cellular circadian rhythms and reveals CKIα as a clock regulatory kinase

Academic Article
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Overview

authors

  • Hirota, T.
  • Lee, Jiing-Dwan
  • Lewis, Warren G
  • Zhang, E. E.
  • Breton, G.
  • Liu, X. Z.
  • Garcia, M.
  • Peters, E. C.
  • Etchegaray, J. P.
  • Traver, D.
  • Schultz, Peter
  • Kay, Steve A.

publication date

  • December 2010

journal

  • PLoS Biology  Journal

abstract

  • The circadian clock underlies daily rhythms of diverse physiological processes, and alterations in clock function have been linked to numerous pathologies. To apply chemical biology methods to modulate and dissect the clock mechanism with new chemical probes, we performed a circadian screen of ∼120,000 uncharacterized compounds on human cells containing a circadian reporter. The analysis identified a small molecule that potently lengthens the circadian period in a dose-dependent manner. Subsequent analysis showed that the compound also lengthened the period in a variety of cells from different tissues including the mouse suprachiasmatic nucleus, the central clock controlling behavioral rhythms. Based on the prominent period lengthening effect, we named the compound longdaysin. Longdaysin was amenable for chemical modification to perform affinity chromatography coupled with mass spectrometry analysis to identify target proteins. Combined with siRNA-mediated gene knockdown, we identified the protein kinases CKIδ, CKIα, and ERK2 as targets of longdaysin responsible for the observed effect on circadian period. Although individual knockdown of CKIδ, CKIα, and ERK2 had small period effects, their combinatorial knockdown dramatically lengthened the period similar to longdaysin treatment. We characterized the role of CKIα in the clock mechanism and found that CKIα-mediated phosphorylation stimulated degradation of a clock protein PER1, similar to the function of CKIδ. Longdaysin treatment inhibited PER1 degradation, providing insight into the mechanism of longdaysin-dependent period lengthening. Using larval zebrafish, we further demonstrated that longdaysin drastically lengthened circadian period in vivo. Taken together, the chemical biology approach not only revealed CKIα as a clock regulatory kinase but also identified a multiple kinase network conferring robustness to the clock. Longdaysin provides novel possibilities in manipulating clock function due to its ability to simultaneously inhibit several key components of this conserved network across species.

subject areas

  • Adenine
  • Animals
  • Biological Clocks
  • CLOCK Proteins
  • Casein Kinase I
  • Cell Line, Tumor
  • Circadian Rhythm
  • Cyclin-Dependent Kinases
  • Gene Expression Regulation
  • Gene Knockdown Techniques
  • Genome-Wide Association Study
  • Histones
  • Humans
  • Mice
  • Mice, Inbred Strains
  • Mitogen-Activated Protein Kinase 1
  • Period Circadian Proteins
  • Protein Kinase Inhibitors
  • Protein Serine-Threonine Kinases
  • RNA Interference
  • Transcription Factors
  • Zebrafish
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Identity

PubMed Central ID

  • PMC3001897

International Standard Serial Number (ISSN)

  • 1544-9173

Digital Object Identifier (DOI)

  • 10.1371/journal.pbio.1000559

PubMed ID

  • 21179498
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Additional Document Info

start page

  • e1000559

volume

  • 8

issue

  • 12

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