SCFFbxl3 controls the oscillation of the circadian clock by directing the degradation of cryptochrome proteins

Science. 2007 May 11;316(5826):900-4. doi: 10.1126/science.1141194. Epub 2007 Apr 26.

Abstract

One component of the circadian clock in mammals is the Clock-Bmal1 heterodimeric transcription factor. Among its downstream targets, two genes, Cry1 and Cry2, encode inhibitors of the Clock-Bmal1 complex that establish a negative-feedback loop. We found that both Cry1 and Cry2 proteins are ubiquitinated and degraded via the SCF(Fbxl3) ubiquitin ligase complex. This regulation by SCF(Fbxl3) is a prerequisite for the efficient and timely reactivation of Clock-Bmal1 and the consequent expression of Per1 and Per2, two regulators of the circadian clock that display tumor suppressor activity. Silencing of Fbxl3 produced no effect in Cry1-/-;Cry2-/- cells, which shows that Fbxl3 controls clock oscillations by mediating the degradation of CRY proteins.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ARNTL Transcription Factors
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • CLOCK Proteins
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cells, Cultured
  • Circadian Rhythm* / genetics
  • Cryptochromes
  • F-Box Proteins / genetics
  • F-Box Proteins / metabolism*
  • Flavoproteins / genetics
  • Flavoproteins / metabolism*
  • HeLa Cells
  • Humans
  • Mice
  • NIH 3T3 Cells
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Period Circadian Proteins
  • Promoter Regions, Genetic
  • RNA Interference
  • SKP Cullin F-Box Protein Ligases / metabolism*
  • Trans-Activators / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transfection
  • Ubiquitin / metabolism

Substances

  • ARNTL Transcription Factors
  • ARNTL protein, human
  • Arntl protein, mouse
  • Basic Helix-Loop-Helix Transcription Factors
  • CRY1 protein, human
  • CRY2 protein, human
  • Cell Cycle Proteins
  • Cry1 protein, mouse
  • Cry2 protein, mouse
  • Cryptochromes
  • F-Box Proteins
  • FBXL3 protein, human
  • Fbxl3 protein, mouse
  • Flavoproteins
  • Nuclear Proteins
  • PER1 protein, human
  • Per1 protein, mouse
  • Per2 protein, mouse
  • Period Circadian Proteins
  • Trans-Activators
  • Transcription Factors
  • Ubiquitin
  • CLOCK Proteins
  • CLOCK protein, human
  • Clock protein, mouse
  • SKP Cullin F-Box Protein Ligases