Metastasis-associated protein 1 is an integral component of the circadian molecular machinery

Nat Commun. 2013;4:2545. doi: 10.1038/ncomms3545.

Abstract

The mammalian circadian clock regulates the daily cycles of many important physiological processes, but its mechanism is not well understood. Here we provide genetic and biochemical evidence that metastasis-associated protein 1 (MTA1), a widely upregulated gene product in human cancers, is an integral component of the circadian molecular machinery. Knockout of MTA1 in mice disrupts the free-running period of circadian rhythms under constant light and normal entrainment of behaviour to 12-h-light/12-h-dark cycles. The CLOCK-BMAL1 heterodimer activates MTA1 transcription through a conserved E-box element at its promoter. MTA1, in turn, interacts with and recruits CLOCK-BMAL1 at its own and CRY1 promoters and promotes their transcription. Moreover, MTA1 deacetylates BMAL1 at lysine 538 through regulating deacetylase SIRT1 expression, thus disturbing the CRY1-mediated negative feedback loop. These findings uncover a previously unappreciated role for MTA1 in maintenance of circadian rhythmicity through acting on the positive limb of the clock machinery.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • ARNTL Transcription Factors / genetics
  • ARNTL Transcription Factors / metabolism
  • Acetylation
  • Animals
  • Behavior, Animal
  • CLOCK Proteins / genetics
  • CLOCK Proteins / metabolism
  • Circadian Rhythm / genetics*
  • Cryptochromes / genetics
  • Cryptochromes / metabolism
  • Feedback, Physiological
  • Female
  • Gene Expression Regulation*
  • Histone Deacetylases / genetics*
  • Histone Deacetylases / metabolism
  • Humans
  • Male
  • Mice
  • Mice, Knockout
  • Motor Activity / genetics
  • Photoperiod
  • Promoter Regions, Genetic
  • Protein Multimerization
  • Repressor Proteins / genetics*
  • Repressor Proteins / metabolism
  • Signal Transduction
  • Sirtuin 1 / genetics
  • Sirtuin 1 / metabolism
  • Transcription Factors / deficiency
  • Transcription Factors / genetics*
  • Transcription, Genetic*

Substances

  • ARNTL Transcription Factors
  • Arntl protein, mouse
  • Cry1 protein, mouse
  • Cryptochromes
  • Mta1 protein, human
  • Mta1 protein, mouse
  • Repressor Proteins
  • Transcription Factors
  • CLOCK Proteins
  • Clock protein, mouse
  • Sirt1 protein, mouse
  • Sirtuin 1
  • Histone Deacetylases