Dec1 and Dec2 are regulators of the mammalian molecular clock

Abstract

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 Per transcription, thus closing the autoregulatory feedback loop. We found that Dec1 and Dec2, basic helix-loop-helix transcription factors, repressed Clock/Bmal1-induced transactivation of the mouse Per1 promoter through direct protein-protein interactions with Bmal1 and/or competition for E-box elements. Dec1 and Dec2 are expressed in the suprachiasmic nucleus in a circadian fashion, with a peak in the subjective day. A brief light pulse induced Dec1 but not Dec2 expression in the suprachiasmic nucleus in a phase-dependent manner. Dec1 and Dec2 are regulators of the mammalian molecular clock, and form a fifth clock-gene family.

Characterization of Peripheral Circadian Clocks in Adipose Tissues

“…Stra13 transcription is activated by CLOCK:BMAL1, whereas the STRA13 protein acts as a repressor of CLOCK:BMAL1 activity (35,36). Maximal levels of Stra13 mRNA in liver have been reported to coincide with the peak of CLOCK: BMAL1 transcriptional activity (25).…”

Assessment of circadian function in fibroblasts of patients with bipolar disorder

“…[45][46][47][48] These negative regulators also suppress the expression of REV-ERBa which inhibits BMAL1 transcription through RORE elements in the BMAL1 promoter. 49,50 Another component of the feedback loop involves DEC1 and DEC2 which repress BMAL1/CLOCK-induced gene transcription, 51 and their functions as clock-controlled genes has also been revealed. 52 In addition, the PAR-leucine zipper transcription factor albumin D element-binding protein (DBP) is a first-order clock-controlled gene directly regulated by BMAL1/ CLOCK; 53 it also plays a role in the core clock by activating Per1 transcription.…”

BHLHB3: a candidate tumor suppressor in lung cancer

“…The basic helix-loop-helix (bHLH) proteins form heterodimers or homodimers via their HLH domains and bind to DNA through a region of basic amino acids immediately N terminal to the HLH dimerization domain (Davis and Turner, 2001). The bHLH transcription factors are involved in coordinated regulation of gene expression and cell differentiation in most mammalian tissues (Honma et al, 2002), affecting neurogenesis, vasculogenesis, mesoderm segmentation, myogenesis and T lymphocyte development (Davis and Turner, 2001). bHLH are targets of the Notch signaling pathway (Davis and Turner, 2001;Iso et al, 2003), which can be dysregulated in a variety of human neoplasms (Davis and Turner, 2001;Allenspach et al, 2002).…”

“…Proteins encoded by the Class B bHLH protein 3 (BHLHB3: also known as DEC2, SHARP-1) gene and its homolog Class B bHLH protein 2 (BHLHB2: also known as DEC1, STRA13, SHARP-2) share 42% total sequence identity and 97% identity in the bHLH region (Fujimoto et al, 2001). Both genes encode bHLH transcriptional repressors involved in the regulation of the mammalian molecular clock (Honma et al, 2002). Retroviral insertional mutagenesis analysis has implicated the mouse Bhlhb3 gene in the development of mouse leukemia/lymphoma (Suzuki et al, 2002).…”