Transactivation mechanisms of mouse clock transcription factors, mClock and mArnt3

Takahata, Sho; Ozaki, Takahiro; Mimura, Junsei; Kikuchi, Yasuo; Sogawa, Kazuhiro; Fujii‐Kuriyama, Yoshiaki

doi:10.1046/j.1365-2443.2000.00363.x

Cited by 92 publications

(101 citation statements)

References 33 publications

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“…2B). These results support a previous study in which the C-terminal region of BMAL1 was shown to be required for its transcriptional activation function (19). Importantly, similar to Flag-BMAL1-Bm29 (Fig.…”

Section: Resultssupporting

confidence: 92%

“…Similar results were obtained when Flag-BMAL1(L554X) was replaced by Flag-BMAL1(E447X) or Flag-BMAL1(I584X) (data not shown). Taken together, these data indicate that the C-terminal 43 aa of BMAL1 protein contain a domain that is essential for mammalian circadian oscillator performance and that, consistent with recent reports that show interaction of p300͞CREB-binding protein coactivators by means of the C-terminal region of BMAL1 (19)(20)(21), this domain must be involved in transcription activation.…”

Section: Resultssupporting

confidence: 90%

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The BMAL1 C terminus regulates the circadian transcription feedback loop

Kiyohara

Tagao

Tamanini

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

103

135

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The circadian clock is driven by cell-autonomous transcription͞ translation feedback loops. The BMAL1 transcription factor is an indispensable component of the positive arm of this molecular oscillator in mammals. Here, we present a molecular genetic screening assay for mutant circadian clock proteins that is based on real-time circadian rhythm monitoring in cultured fibroblasts. By using this assay, we identified a domain in the extreme C terminus of BMAL1 that plays an essential role in the rhythmic control of E-box-mediated circadian transcription. Remarkably, the last 43 aa of BMAL1 are required for transcriptional activation, as well as for association with the circadian transcriptional repressor CRYPTO-CHROME 1 (CRY1), depending on the coexistence of CLOCK protein. C-terminally truncated BMAL1 mutant proteins still associate with mPER2 (another protein of the negative feedback loop), suggesting that an additional repression mechanism may converge on the N terminus. Taken together, these results suggest that the C-terminal region of BMAL1 is involved in determining the balance between circadian transcriptional activation and suppression.circadian clock ͉ real-time monitor T he mammalian circadian clock is a highly dynamic system that generates periodic fluctuations in the mRNA expression levels of hundreds of genes to confer near 24-h rhythmicity to behavior, physiology, and metabolic processes, thereby allowing mammals to anticipate the momentum of the day (1). The master clock resides in the suprachiasmatic nuclei (SCN) of the brain and, in turn, synchronizes circadian clocks in peripheral tissues (2). Even fibroblasts in culture contain an active circadian clock that has the same genetic makeup of the central clock in the SCN (3-6). To keep pace with the day-night cycle, the SCN clock, but not peripheral clocks, are entrained by light.Circadian rhythms are generated by a molecular oscillator that consists of intertwined positive and negative transcription͞ translation feedback loops involving a set of clock genes (7) and clock-controlled output genes that link the oscillator to clockcontrolled processes (8). BMAL1 (MOP3) and CLOCK are basic helix-loop-helix PAS transcription factors that heterodimerize and (by means of binding to E-box promoter elements) transactivate the Period (Per1 and Per2) and Cryptochrome (Cry1 and Cry2) genes and an orphan nuclear receptor Rev-Erb␣ core oscillator gene. Subsequently, PER and CRY proteins act as negative elements by inhibiting the activity of the CLOCK͞BMAL1 heterodimer, whereas REV-ERB␣ negatively regulates Bmal1 gene expression (1, 9). The above feedback mechanism is supported by biochemical, molecular, and genetic evidence; however, formal proof of its requirement in the maintenance of circadian clock oscillations has not been shown thus far.Genetic ablation of mBmal1 results in complete disruption of the mammalian circadian clock at the behavioral and molecular levels (10). However, except for the PAS elements, which are required for association with CLOCK (11)...

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Section: Resultssupporting

confidence: 92%

Section: Resultssupporting

confidence: 90%

The BMAL1 C terminus regulates the circadian transcription feedback loop

Kiyohara

Tagao

Tamanini

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

103

135

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“…This Cterminal end of mBMAL1 was previously implicated in transcriptional activation in both yeast and mammalian cell culture (22). The authors of that study suggested that the C terminus of mBMAL1 is the primary transactivation domain of mCLK: mBMAL1, and that the C terminus of mCLK may serve only to augment or stabilize the activity of mBMAL1 (22). The conservation of this BMAL C-terminal region ("BCTR") in apBMAL suggests that apBMAL may also possess a C-terminal transactivation domain.…”

Section: Resultsmentioning

confidence: 97%

“…Because the mutant mCLK protein (mCLK⌬19) is defective for transcriptional activation (21), this region may be an important part of the transactivation domain, even though it does not contain polyglutamine stretches. Alternatively, the "⌬19" region may be involved in stabilizing the CLK:BMAL heterodimer (22), or function as a binding site for important regulatory proteins, such as PER (see below).…”

Section: Resultsmentioning

confidence: 99%

“…The gray bar represents primary amino acid sequence of each protein (to scale). White box with "bH " ϭ basic helix-loop-helix (bHLH) domain; remaining white boxes ϭ parts of the PAS domain labeled "A" (PAS-A), "B" (PAS-B), and "C" (PAC); gray box with "T " ϭ region homologous to the transactivation domain of mBMAL1 (22); called the BMAL C-terminal region (BCTR) in the text. In the sequence of the BCTR of apBMAL and mBMAL1, identical amino acids are marked black and similar amino acids are light gray.…”

Section: Resultsmentioning

confidence: 99%

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Constructing a Feedback Loop with Circadian Clock Molecules from the Silkmoth, Antheraea pernyi

Chang

McWatters

Williams

et al. 2003

Journal of Biological Chemistry

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Circadian clocks are important regulators of behavior and physiology. The circadian clock of Drosophila depends on an autoinhibitory feedback loop involving dCLOCK, CYCLE (also called dBMAL, for Drosophila brain and muscle ARNT-like protein), dPERIOD, and dTIMELESS. Recent studies suggest that the clock mechanism in other insect species may differ strikingly from that of Drosophila. We cloned Clock, Bmal, and Timeless homologs (apClock, apBmal, and apTimeless) from the silkmoth Antheraea pernyi, from which a Period homolog (apPeriod) has already been cloned. In Schneider 2 (S2) cell culture assays, apCLOCK:apBMAL activates transcription through an E-box enhancer element found in the 5 region of the apPeriod gene. Furthermore, apPERIOD can robustly inhibit apCLOCK: apBMAL-mediated transactivation, and apTIMELESS can augment this inhibition. Thus, a complete feedback loop, resembling that found in Drosophila, can be constructed from silkmoth CLOCK, BMAL, PERIOD, and TIMELESS. Our results suggest that the circadian autoinhibitory feedback loop discovered in Drosophila is likely to be widespread among insects. However, whereas the transactivation domain in Drosophila lies in the C terminus of dCLOCK, in A. pernyi, it lies in the C terminus of apBMAL, which is highly conserved with the C termini of BMALs in other insects (except Drosophila) and in vertebrates. Our analysis sheds light on the molecular function and evolution of clock genes in the animal kingdom.

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Circadian Rhythms in Liver Physiology and Liver Diseases

Tong

Yin

2013

Comprehensive Physiology

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In mammals, circadian rhythms function to coordinate a diverse panel of physiological processes with environmental conditions such as food and light. As the driving force for circadian rhythmicity, the molecular clock is a self-sustained transcription-translational feedback loop system consisting of transcription factors, epigenetic modulators, kinases/phosphatases, and ubiquitin E3 ligases. The molecular clock exists not only in the suprachiasmatic nuclei of the hypothalamus but also in the peripheral tissues to regulate cellular and physiological function in a tissue-specific manner. The circadian clock system in the liver plays important roles in regulating metabolism and energy homeostasis. Clock gene mutant animals display impaired glucose and lipid metabolism and are susceptible to diet-induced obesity and metabolic dysfunction, providing strong evidence for the connection between the circadian clock and metabolic homeostasis. Circadian-controlled hepatic metabolism is partially achieved by controlling the expression and/or activity of key metabolic enzymes, transcription factors, signaling molecules, and transporters. Reciprocally, intracellular metabolites modulate the molecular clock activity in response to the energy status. Although still at the early stage, circadian clock dysfunction has been implicated in common chronic liver diseases. Circadian dysregulation of lipid metabolism, detoxification, reactive oxygen species (ROS) production, and cell-cycle control might contribute to the onset and progression of liver steatosis, fibrosis, and even carcinogenesis. In summary, these findings call for a comprehensive study of the function and mechanisms of hepatic circadian clock to gain better understanding of liver physiology and diseases.

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Transactivation mechanisms of mouse clock transcription factors, mClock and mArnt3

Abstract: Background: The Arnt3 (also termed as BMAL1 or MOP3)/Clock heterodimer is a positive regulator of circadian rhythm and activates the transcription of target genes such as per1 and vasopressin.

Cited by 92 publications

References 33 publications

The BMAL1 C terminus regulates the circadian transcription feedback loop

The BMAL1 C terminus regulates the circadian transcription feedback loop

Constructing a Feedback Loop with Circadian Clock Molecules from the Silkmoth, Antheraea pernyi

Circadian Rhythms in Liver Physiology and Liver Diseases

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