CIPC is a mammalian circadian clock protein without invertebrate homologues

Nat Cell Biol. 2007 Mar;9(3):268-75. doi: 10.1038/ncb1539. Epub 2007 Feb 18.

Abstract

At the core of the mammalian circadian clock is a feedback loop in which the heterodimeric transcription factor CLOCK-Brain, Muscle Arnt-like-1 (BMAL1) drives expression of its negative regulators, periods (PERs) and cryptochromes (CRYs). Here, we provide evidence that CLOCK-Interacting Protein, Circadian (CIPC) is an additional negative-feedback regulator of the circadian clock. CIPC exhibits circadian regulation in multiple tissues, and it is a potent and specific inhibitor of CLOCK-BMAL1 activity that functions independently of CRYs. CIPC-CLOCK protein complexes are present in vivo, and depletion of endogenous CIPC shortens the circadian period length. CIPC is unrelated to known proteins and has no recognizable homologues outside vertebrates. Our results suggest that negative feedback in the mammalian circadian clock is divided into distinct pathways, and that the addition of new genes has contributed to the complexity of vertebrate clocks.

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 / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Biological Clocks / physiology*
  • CLOCK Proteins
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cell Nucleus / chemistry
  • Cell Nucleus / metabolism
  • Circadian Rhythm / physiology*
  • Cryptochromes
  • Flavoproteins / genetics
  • Flavoproteins / metabolism
  • Gene Expression Regulation
  • Immunoprecipitation
  • Kidney / metabolism
  • Liver / metabolism
  • Mammals / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mutation
  • Myocardium / metabolism
  • NIH 3T3 Cells
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism
  • Period Circadian Proteins
  • Protein Binding
  • RNA, Antisense / genetics
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Transcriptional Activation / genetics
  • Transfection
  • Two-Hybrid System Techniques

Substances

  • ARNTL Transcription Factors
  • Arntl protein, mouse
  • Basic Helix-Loop-Helix Transcription Factors
  • CIPC protein, mouse
  • Carrier Proteins
  • Cell Cycle Proteins
  • Cryptochromes
  • Flavoproteins
  • Nuclear Proteins
  • Peptide Fragments
  • Per1 protein, mouse
  • Period Circadian Proteins
  • RNA, Antisense
  • Trans-Activators
  • CLOCK Proteins
  • Clock protein, mouse