Dec1 and Dec2 are regulators of the mammalian molecular clock

  title={Dec1 and Dec2 are regulators of the mammalian molecular clock},
  author={Sato Honma and Takeshi Kawamoto and Yumi Takagi and Katsumi Fujimoto and Fuyuki Sato and Mitsuhide Noshiro and Yukio Kato and Ken-ichi Honma},
The circadian rhythms in mammals are regulated by a pacemaker located in the suprachiasmatic nucleus of the hypothalamus. Four clock-gene families have been found to be involved in a transcription–translation feedback loop that generates the circadian rhythm at the intracellular level. The proteins Clock and Bmal1 form a heterodimer which activates the transcription of the Per gene from the E-box elements in its promoter region. Protein products of Per act together with Cry proteins to inhibit… 
A novel autofeedback loop of Dec1 transcription involved in circadian rhythm regulation.
DEC2–E4BP4 Heterodimer Represses the Transcriptional Enhancer Activity of the EE Element in the Per2 Promoter
E4BP4 binds to the Per2 EE element with DEC2 to repress transcription and is identified as a key repressor of the tightly interlocked Per2 feedback loop in the mammalian circadian oscillator, suggesting an additional modulatory mechanism for tuning of the phase of cell-autonomous Per2 gene expression cycling.
Light does not degrade the constitutively expressed BMAL1 protein in the mouse suprachiasmatic nucleus
The study shows that BMAL1 and CLOCK proteins are continuously expressed at high levels in the mouse SCN, supporting the hypothesis that rhythmic negative feedback plays the major role in rhythm generation in the mammalian pacemaker and indicating that rapid degradation of BMAL 1 protein is not a consistent feature of resetting mechanisms in rodents.
Dec1 and Dec2 Expression is Disrupted in the Suprachiasmatic Nuclei of Clock Mutant Mice
DEC1 and DEC2 can inhibit CLOCK:BMAL1 transactivation of the clock gene Per1, suggesting that these transcription factors may help regulate circadian timing, and data point to up-regulation of Dec1 and Dec2 by Clock in vivo.
Transcriptional feedback loops in the ovine circadian clock.
CIPC-dependent phosphorylation of CLOCK and NPAS2 in circadian clockwork
It is strongly suggested that the BMAL1-dependent and CIPC-stimulated phosphorylation of CLOCK and possibly NPAS2 represents an important regulatory mechanism underlying the circadian gene expression mediated by these transcription factor members.
Expression of the gene for Dec2, a basic helix-loop-helix transcription factor, is regulated by a molecular clock system.
It is shown that transcription of the Dec2 gene is regulated by several clock molecules and a negative-feedback loop, and that the Clock/Bmal heterodimer enhances Dec2 transcription via the CACGTG E-boxes, whereas the induced transcription is suppressed by Dec2, which therefore must contribute to its own rhythmic expression.
Circadian Rhythm: A Functional Connection Between SHP and DEC1 Transcription Factor
It is established that DEC1 constitutes the negative loop of the SHP oscillating expression and that the DEC1-SHP pathway is intimately involved in energy homeostasis with profound pathophysiologic significance.
The Transcriptional Repressor STRA13 Regulates a Subset of Peripheral Circadian Outputs*
Central and peripheral mammalian circadian clocks regulate a variety of behavioral and physiological processes through the rhythmic transcription of hundreds of clock-controlled genes. The circadian


Bimodal regulation of mPeriod promoters by CREB-dependent signaling and CLOCK/BMAL1 activity
The results reveal that signaling-dependent activation of mPer genes is distinct from the CLOCK/BMAL1-driven transcription required within the clock feedback loop, and constitute strong evidence that CREB acts as a pivotal endpoint of signaling pathways for the regulation of m per genes.
Circadian oscillation of BMAL1, a partner of a mammalian clock gene Clock, in rat suprachiasmatic nucleus.
A superfamily gene which encodes a bHLH (basic helix-loop-helix)/PAS transcription factor, BMAL1, was cloned and sequenced from rat cDNA and possibly plays a critical role in the clock mechanism generating the circadian oscillation in rats.
Interactivating feedback loops within the mammalian clock: BMAL1 is negatively autoregulated and upregulated by CRY1, CRY2, and PER2.
The transcriptional potency of CRY is predominant within the mammalian clock, suggesting a clearance mechanism for CRY in period maintenance, and it is proposed that a BMAL1 negative feedback loop interlocks with the CRY and PER2negative feedback loop by inter-activation, forming a third positive forward loop.
Closing the circadian loop: CLOCK-induced transcription of its own inhibitors per and tim.
The Drosophila CLOCK protein was shown to induce transcription of the circadian rhythm genes period and timeless, and PERIOD and TIMELESS proteins blocked dCLOCK's ability to transactivate their promoters via the E-box.
Interacting molecular loops in the mammalian circadian clock.
Analysis of Clock/Clock mutant mice, homozygous Period2(Brdm1) mutants, and Cryptochrome-deficient mice reveals substantially altered Bmal1 rhythms, consistent with a dominant role of PERIOD2 in the positive regulation of the Bmal 1 loop.
Molecular analysis of mammalian circadian rhythms.
Greater understanding of the cellular and molecular mechanisms of the SCN clockwork provides opportunities for pharmacological manipulation of circadian timing.
Dimerization and nuclear entry of mPER proteins in mammalian cells.
It is reported that nuclear translocation of mPER1 and mPER2 involves physical interactions with mPER3, is accelerated by serum treatment, and still occurs in mCry1/mCry2 double-deficient cells lacking a functional biological clock.
Antagonistic role of E4BP4 and PAR proteins in the circadian oscillatory mechanism.
It is shown that the phase of e4bp4 mRNA rhythm is opposite to that of the dbp, hlf, and tef rhythms in the suprachiasmatic nucleus (SCN), the mammalian circadian center, and the liver, and that the protein levels of E4BP4 and DBP fluctuate in almost the opposite phase.