mCRY1 and mCRY2 are essential components of the negative limb of the circadian clock feedback loop

Cell. 1999 Jul 23;98(2):193-205. doi: 10.1016/s0092-8674(00)81014-4.

Abstract

We determined that two mouse cryptochrome genes, mCry1 and mCry2, act in the negative limb of the clock feedback loop. In cell lines, mPER proteins (alone or in combination) have modest effects on their cellular location and ability to inhibit CLOCK:BMAL1 -mediated transcription. This suggested cryptochrome involvement in the negative limb of the feedback loop. Indeed, mCry1 and mCry2 RNA levels are reduced in the central and peripheral clocks of Clock/Clock mutant mice. mCRY1 and mCRY2 are nuclear proteins that interact with each of the mPER proteins, translocate each mPER protein from cytoplasm to nucleus, and are rhythmically expressed in the suprachiasmatic circadian clock. Luciferase reporter gene assays show that mCRY1 or mCRY2 alone abrogates CLOCK:BMAL1-E box-mediated transcription. The mPER and mCRY proteins appear to inhibit the transcriptional complex differentially.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3T3 Cells
  • ARNTL Transcription Factors
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors
  • Biological Clocks / physiology*
  • Blotting, Western
  • CLOCK Proteins
  • COS Cells
  • Cell Cycle Proteins
  • Cell Nucleus / metabolism
  • Cloning, Molecular
  • Cryptochromes
  • Drosophila Proteins*
  • Eye Proteins*
  • Feedback / physiology
  • Female
  • Flavoproteins / analysis
  • Flavoproteins / genetics*
  • Flavoproteins / metabolism
  • Gene Expression / physiology
  • Humans
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Molecular Sequence Data
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Period Circadian Proteins
  • Photoreceptor Cells, Invertebrate*
  • RNA, Messenger / metabolism
  • Receptors, G-Protein-Coupled
  • Suprachiasmatic Nucleus / chemistry
  • Suprachiasmatic Nucleus / metabolism
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcription, Genetic / physiology

Substances

  • ARNTL Transcription Factors
  • BMAL1 protein, human
  • Bmal1 protein, mouse
  • Basic Helix-Loop-Helix Transcription Factors
  • Cell Cycle Proteins
  • Cryptochromes
  • Drosophila Proteins
  • Eye Proteins
  • Flavoproteins
  • Nuclear Proteins
  • PER1 protein, human
  • PER2 protein, human
  • Per1 protein, mouse
  • Per2 protein, mouse
  • Period Circadian Proteins
  • RNA, Messenger
  • Receptors, G-Protein-Coupled
  • Trans-Activators
  • Transcription Factors
  • cry protein, Drosophila
  • CLOCK Proteins
  • CLOCK protein, human
  • Clock protein, mouse

Associated data

  • GENBANK/AF156987