Interacting selectively and non-covalently with any of the basic Helix-Loop-Helix (bHLH) superfamily of transcription factors, important regulatory components in transcriptional networks of many developmental pathways.
Evidence
1:
Inferred from Physical InteractionBHF-UCL
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.
Evidence
2:
Inferred from Physical InteractionBHF-UCL
DEC1 (differentially expressed in chondrocytes 1) and DEC2 are E-box-binding transcription factors and exhibit a circadian expression pattern. Recently, both proteins were found to repress the Clock/Bmal1-activated E-box promoters (e.g. mPer1). Yeast two-hybrid assay detected interactions between Bmal1 and DECs. It was hypothesized that DEC-mediated repression on the mPer1 promoter is achieved by binding to E-box elements and interacting with Bmal1. In the present study, we report that E-box binding rather than Bmal1 interaction is responsible for the observed repression. In the absence of Clock/Bmal1, both DEC1 and DEC2 markedly repressed the mPer1 promoter reporter; however, DNA-binding mutants showed no repressive activity. Similarly, DEC1, but not its DNA-binding mutants, repressed the Clock/Bmal1-induced activation. In addition, DEC1(R58P), a DNA-binding mutant with Bmal1 interactivity, repressed neither the mPer1 reporter directly nor the Clock/Bmal1-induced activation, providing direct evidence that DNA binding, rather than Bmal1 interactions, is responsible for the repression on the mPer1 promoter. Furthermore, disruption of the Sp1 site in the proximal promoter of mPer1 increased the repression of DEC1 proteins. Previous studies with mouse DEC2 showed that this factor interacts with Sp1. These findings suggest that DEC proteins regulate the expression of mPer1 through E-box binding and Sp1 interaction. Alterations on circadian systems are increasingly recognized as important risk factors for disease initiation and progression, and the expression of Dec genes is rapidly induced by environmental stimuli and is highly increased in tumour tissues. Therefore de-regulated expression of DEC genes probably alters normal circadian rhythms and contributes significantly to the pathogenesis of many diseases including cancer.
Interacting selectively and non-covalently with an E-box, a DNA motif with the consensus sequence CANNTG that is found in the promoters of a wide array of genes expressed in neurons, muscle and other tissues.
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.
DEC1 (differentially expressed in chondrocytes 1) and DEC2 are E-box-binding transcription factors and exhibit a circadian expression pattern. Recently, both proteins were found to repress the Clock/Bmal1-activated E-box promoters (e.g. mPer1). Yeast two-hybrid assay detected interactions between Bmal1 and DECs. It was hypothesized that DEC-mediated repression on the mPer1 promoter is achieved by binding to E-box elements and interacting with Bmal1. In the present study, we report that E-box binding rather than Bmal1 interaction is responsible for the observed repression. In the absence of Clock/Bmal1, both DEC1 and DEC2 markedly repressed the mPer1 promoter reporter; however, DNA-binding mutants showed no repressive activity. Similarly, DEC1, but not its DNA-binding mutants, repressed the Clock/Bmal1-induced activation. In addition, DEC1(R58P), a DNA-binding mutant with Bmal1 interactivity, repressed neither the mPer1 reporter directly nor the Clock/Bmal1-induced activation, providing direct evidence that DNA binding, rather than Bmal1 interactions, is responsible for the repression on the mPer1 promoter. Furthermore, disruption of the Sp1 site in the proximal promoter of mPer1 increased the repression of DEC1 proteins. Previous studies with mouse DEC2 showed that this factor interacts with Sp1. These findings suggest that DEC proteins regulate the expression of mPer1 through E-box binding and Sp1 interaction. Alterations on circadian systems are increasingly recognized as important risk factors for disease initiation and progression, and the expression of Dec genes is rapidly induced by environmental stimuli and is highly increased in tumour tissues. Therefore de-regulated expression of DEC genes probably alters normal circadian rhythms and contributes significantly to the pathogenesis of many diseases including cancer.
Human DEC (differentially expressed in chondrocytes), mouse STRA (stimulated with retinoic acid), and rat SHARP (split and hairy related protein) proteins constitute a new and structurally distinct class of the basic helix-loop-helix proteins. In each species, two members are identified with a sequence identity of >90% in the basic helix-loop-helix region and approximately 40% in the total proteins, respectively. Recently, we have reported that DEC1 is abundantly expressed in colon carcinomas but not in the adjacent normal tissues. The present study was undertaken to extend the expression study of DEC1 and to determine whether DEC1 and DEC2 had similar expression patterns among paired cancer-normal tissues from the colon, lung, and kidney. Without exceptions, DEC1 was markedly higher in the carcinomas, whereas the opposite was true with DEC2. In stable transfectants, tetracycline-induced expression of DEC1 caused proportional decreases in the expression of DEC2. Co-transfection with DEC1 repressed the activity of a DEC2 promoter reporter by as much as 90%. The repression was observed with wild type DEC1 but not its DNA binding-defective mutants. Studies with deletion and site-directed mutants located, in the proximal promoter, an E-box motif that supported the DEC1-mediated repression. Disruption of this E-box markedly abolished the ability of the reporter to respond to DEC1. Our findings assign for DEC1 the first target gene that is regulated through direct DNA binding. DEC/STRA/SHARP proteins are highly identical in the DNA binding domain but much more diverse in other areas. DEC1-mediated repression on the expression of DEC2 provides an important mechanism that these transcription factors regulate the cellular function not only by modulating the expression of their target genes but also the expression of members within the same class.
DEC1 suppresses CLOCK/BMAL1-enhanced promoter activity, but its role in the circadian system of mammals remains unclear. Here we examined the effect of Dec1 overexpression or deficiency on circadian gene expression triggered with 50% serum. Overexpression of Dec1 delayed the phase of clock genes such as Dec1, Dec2, Per1, and Dbp that contain E boxes in their regulatory regions, whereas it had little effect on the circadian phase of Per2 and Cry1 carrying CACGTT E' boxes. In contrast, Dec1 deficiency advanced the phase of the E-box-containing clock genes but not that of the E'-box-containing clock genes. Accordingly, DEC1 showed strong binding and transrepression on the E box, but not on the E' box, in chromatin immunoprecipitation, electrophoretic mobility shift, and luciferase reporter assays. Dec1-/- mice showed behavioral rhythms with slightly but significantly longer circadian periods under conditions of constant darkness and faster reentrainment to a 6-h phase-advanced shift of a light-dark cycle. Knockdown of Dec2 with small interfering RNA advanced the phase of Dec1 and Dbp expression, and double knockdown of Dec1 and Dec2 had much stronger effects on the expression of the E-box-containing clock genes. These findings suggest that DEC1, along with DEC2, plays a role in the finer regulation and robustness of the molecular clock.
The basic helix-loop-helix transcription factor DEC1 is expressed in a circadian manner in the suprachiasmatic nucleus where it seems to play a role in regulating the mammalian circadian rhythm by suppressing the CLOCK/BMAL1-activated promoter. The interaction of DEC1 with BMAL1 has been suggested as one of the molecular mechanisms of the suppression [Honma, S., Kawamoto, T., Takagi, Y., Fujimoto, K., Sato, F., Noshiro, M., Kato, Y. & Honma, K. (2002) Nature 419, 841-844]. Deletion analysis of DEC1 demonstrated that its N-terminal region, which includes the basic helix-loop-helix domain, was essential for both the suppressive activity and the interaction with BMAL1, as DEC1 lacking the basic region did not show any suppression or interaction. Furthermore, we found that Arg65 in the basic region, which is conserved among group B basic helix-loop-helix proteins, was responsible for the suppression, for the interaction with BMAL1 and for its binding to CACGTG E-boxes. However, substitution of His57 for Ala significantly reduced the E-box binding activity of DEC1, although it did not affect the interaction with BMAL1 or suppression of CLOCK/BMAL1-induced transcription. On the other hand, the basic region-deleted DEC1 acted in a dominant-negative manner for DEC1 activity, indicating that the basic region was not required for homodimer formation of DEC1. Moreover, mutant DEC1 also counteracted DEC2-mediated suppressive activity in a dominant-negative manner. The heterodimer formation of DEC1 and DEC2 was confirmed by pull-down assay. These findings suggest that the basic region of DEC1 participates in the transcriptional regulation through a protein-protein interaction with BMAL1 and DNA binding to the E-box.
An autofeedback loop associated with transcription of clock gene(s), Per(s), is generally accepted as the molecular machinery of circadian rhythm generation, in which CLOCK/BMAL act as positive regulators and PER/CRY as negative ones. We show here an autofeedback loop of Dec1 encoding a basic helix-loop-helix transcription factor: CLOCK/BMAL increased the promoter activity of Dec1, and DEC1 and DEC2 as well as PERs and CRYs suppressed the induced expression. Three CACGTG E-boxes are responsible for both the activation and the suppression of Dec1 transcription. Forced expression of Clock/Bmal increased endogenous Dec1 mRNA level, and overexpression of Dec1 resulted in suppression of Dec2, Per2, and Dbp expression. The level of Dec1 expression in the heart of Clock/Clock mutant mice was continuously low throughout the day. These findings suggest that Dec1 is positively regulated by CLOCK/BMAL and is involved in circadian rhythm regulation by suppressing CLOCK/BMAL-induced gene expression. The autofeedback loop of Dec1 may be interlocked with the core feedback loop of Per in some situations.
Interacting selectively and non-covalently with Myogenic Regulatory Factor (MRF), a member of the basic Helix-Loop-Helix (bHLH) superfamily of transcription factors.
Interacting selectively and non-covalently with any protein or protein complex (a complex of two or more proteins that may include other nonprotein molecules).
Evidence
1:
Inferred from Physical InteractionIntAct
In this study, we focus on different modes of regulation of STRA13, a human ortholog of the mouse basic helix-loop-helix transcriptional factor, previously identified by us as a new von Hippel-Lindau tumor suppressor gene (VHL) target. The gene was overexpressed in VHL-deficient cell lines and tumors, specifically clear cell renal carcinomas and hemangioblastomas. Introduction of wild type VHL transgene into clear cell renal carcinoma restored low level expression of STRA13. Overexpression was also detected in many common malignancies with an intact VHL gene, suggesting the existence of another, VHL-independent pathway of STRA13 regulation. Similar to many other von Hippel-Lindau tumor-suppressor protein (pVHL) targets, the expression of STRA13 on the mRNA level was hypoxia-sensitive, indicating oxygen-dependent regulation of the gene, presumably through the pVHL/hypoxia-inducible factor 1 (HIF-1) pathway. The yeast two-hybrid screening revealed interaction of the STRA13 protein with the human ubiquitin-conjugating enzyme (UBC9) protein, the specificity of which was confirmed in mammalian cells. By adding the proteasome inhibitor acetyl-leucinyl-leucinyl-norleucinal, we demonstrated that the 26 S proteasome pathway regulates the stability of pSTRA13. Co-expression of STRA13 and UBC9 led to an increase of the pSTRA13 ubiquitination and subsequent degradation. These data established that UBC9/STRA13 association in cells is of physiological importance, presenting direct proof of UBC9 involvement in the ubiquitin-dependent degradation of pSTRA13. Hypoxia treatment of mammalian cells transiently expressing STRA13 protein showed that stability of pSTRA13 is not affected by hypoxia or VHL. Thus, STRA13, a new pVHL target, is regulated in cells on multiple levels. We propose that STRA13 may play a critical role in carcinogenesis, since it is a potent transcriptional regulator, abundant in a variety of common tumors.
The basic helix-loop-helix transcription factor DEC1 is expressed in a circadian manner in the suprachiasmatic nucleus where it seems to play a role in regulating the mammalian circadian rhythm by suppressing the CLOCK/BMAL1-activated promoter. The interaction of DEC1 with BMAL1 has been suggested as one of the molecular mechanisms of the suppression [Honma, S., Kawamoto, T., Takagi, Y., Fujimoto, K., Sato, F., Noshiro, M., Kato, Y. & Honma, K. (2002) Nature 419, 841-844]. Deletion analysis of DEC1 demonstrated that its N-terminal region, which includes the basic helix-loop-helix domain, was essential for both the suppressive activity and the interaction with BMAL1, as DEC1 lacking the basic region did not show any suppression or interaction. Furthermore, we found that Arg65 in the basic region, which is conserved among group B basic helix-loop-helix proteins, was responsible for the suppression, for the interaction with BMAL1 and for its binding to CACGTG E-boxes. However, substitution of His57 for Ala significantly reduced the E-box binding activity of DEC1, although it did not affect the interaction with BMAL1 or suppression of CLOCK/BMAL1-induced transcription. On the other hand, the basic region-deleted DEC1 acted in a dominant-negative manner for DEC1 activity, indicating that the basic region was not required for homodimer formation of DEC1. Moreover, mutant DEC1 also counteracted DEC2-mediated suppressive activity in a dominant-negative manner. The heterodimer formation of DEC1 and DEC2 was confirmed by pull-down assay. These findings suggest that the basic region of DEC1 participates in the transcriptional regulation through a protein-protein interaction with BMAL1 and DNA binding to the E-box.
The basic helix-loop-helix transcription factor DEC1 is expressed in a circadian manner in the suprachiasmatic nucleus where it seems to play a role in regulating the mammalian circadian rhythm by suppressing the CLOCK/BMAL1-activated promoter. The interaction of DEC1 with BMAL1 has been suggested as one of the molecular mechanisms of the suppression [Honma, S., Kawamoto, T., Takagi, Y., Fujimoto, K., Sato, F., Noshiro, M., Kato, Y. & Honma, K. (2002) Nature 419, 841-844]. Deletion analysis of DEC1 demonstrated that its N-terminal region, which includes the basic helix-loop-helix domain, was essential for both the suppressive activity and the interaction with BMAL1, as DEC1 lacking the basic region did not show any suppression or interaction. Furthermore, we found that Arg65 in the basic region, which is conserved among group B basic helix-loop-helix proteins, was responsible for the suppression, for the interaction with BMAL1 and for its binding to CACGTG E-boxes. However, substitution of His57 for Ala significantly reduced the E-box binding activity of DEC1, although it did not affect the interaction with BMAL1 or suppression of CLOCK/BMAL1-induced transcription. On the other hand, the basic region-deleted DEC1 acted in a dominant-negative manner for DEC1 activity, indicating that the basic region was not required for homodimer formation of DEC1. Moreover, mutant DEC1 also counteracted DEC2-mediated suppressive activity in a dominant-negative manner. The heterodimer formation of DEC1 and DEC2 was confirmed by pull-down assay. These findings suggest that the basic region of DEC1 participates in the transcriptional regulation through a protein-protein interaction with BMAL1 and DNA binding to the E-box.
Evidence
2:
Inferred from Physical InteractionBHF-UCL
DEC1 (differentially expressed in chondrocytes 1) and DEC2 are E-box-binding transcription factors and exhibit a circadian expression pattern. Recently, both proteins were found to repress the Clock/Bmal1-activated E-box promoters (e.g. mPer1). Yeast two-hybrid assay detected interactions between Bmal1 and DECs. It was hypothesized that DEC-mediated repression on the mPer1 promoter is achieved by binding to E-box elements and interacting with Bmal1. In the present study, we report that E-box binding rather than Bmal1 interaction is responsible for the observed repression. In the absence of Clock/Bmal1, both DEC1 and DEC2 markedly repressed the mPer1 promoter reporter; however, DNA-binding mutants showed no repressive activity. Similarly, DEC1, but not its DNA-binding mutants, repressed the Clock/Bmal1-induced activation. In addition, DEC1(R58P), a DNA-binding mutant with Bmal1 interactivity, repressed neither the mPer1 reporter directly nor the Clock/Bmal1-induced activation, providing direct evidence that DNA binding, rather than Bmal1 interactions, is responsible for the repression on the mPer1 promoter. Furthermore, disruption of the Sp1 site in the proximal promoter of mPer1 increased the repression of DEC1 proteins. Previous studies with mouse DEC2 showed that this factor interacts with Sp1. These findings suggest that DEC proteins regulate the expression of mPer1 through E-box binding and Sp1 interaction. Alterations on circadian systems are increasingly recognized as important risk factors for disease initiation and progression, and the expression of Dec genes is rapidly induced by environmental stimuli and is highly increased in tumour tissues. Therefore de-regulated expression of DEC genes probably alters normal circadian rhythms and contributes significantly to the pathogenesis of many diseases including cancer.
Evidence
3:
Inferred from Physical InteractionBHF-UCL
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.
The basic helix-loop-helix transcription factor DEC1 is expressed in a circadian manner in the suprachiasmatic nucleus where it seems to play a role in regulating the mammalian circadian rhythm by suppressing the CLOCK/BMAL1-activated promoter. The interaction of DEC1 with BMAL1 has been suggested as one of the molecular mechanisms of the suppression [Honma, S., Kawamoto, T., Takagi, Y., Fujimoto, K., Sato, F., Noshiro, M., Kato, Y. & Honma, K. (2002) Nature 419, 841-844]. Deletion analysis of DEC1 demonstrated that its N-terminal region, which includes the basic helix-loop-helix domain, was essential for both the suppressive activity and the interaction with BMAL1, as DEC1 lacking the basic region did not show any suppression or interaction. Furthermore, we found that Arg65 in the basic region, which is conserved among group B basic helix-loop-helix proteins, was responsible for the suppression, for the interaction with BMAL1 and for its binding to CACGTG E-boxes. However, substitution of His57 for Ala significantly reduced the E-box binding activity of DEC1, although it did not affect the interaction with BMAL1 or suppression of CLOCK/BMAL1-induced transcription. On the other hand, the basic region-deleted DEC1 acted in a dominant-negative manner for DEC1 activity, indicating that the basic region was not required for homodimer formation of DEC1. Moreover, mutant DEC1 also counteracted DEC2-mediated suppressive activity in a dominant-negative manner. The heterodimer formation of DEC1 and DEC2 was confirmed by pull-down assay. These findings suggest that the basic region of DEC1 participates in the transcriptional regulation through a protein-protein interaction with BMAL1 and DNA binding to the E-box.
Interacting selectively and non-covalently with an RNA polymerase II transcription activating factor, a protein involved in positive regulation of transcription.
ISSOrtholog Curator
RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity involved in negative regulation of transcriptiondefinition[GO:0001078]
Interacting selectively and non-covalently with a sequence of DNA that is in cis with and relatively close to a core promoter for RNA polymerase II (RNAP II) in order to stop, prevent, or reduce the frequency, rate or extent of transcription from an RNA polymerase II promoter.
Human DEC (differentially expressed in chondrocytes), mouse STRA (stimulated with retinoic acid), and rat SHARP (split and hairy related protein) proteins constitute a new and structurally distinct class of the basic helix-loop-helix proteins. In each species, two members are identified with a sequence identity of >90% in the basic helix-loop-helix region and approximately 40% in the total proteins, respectively. Recently, we have reported that DEC1 is abundantly expressed in colon carcinomas but not in the adjacent normal tissues. The present study was undertaken to extend the expression study of DEC1 and to determine whether DEC1 and DEC2 had similar expression patterns among paired cancer-normal tissues from the colon, lung, and kidney. Without exceptions, DEC1 was markedly higher in the carcinomas, whereas the opposite was true with DEC2. In stable transfectants, tetracycline-induced expression of DEC1 caused proportional decreases in the expression of DEC2. Co-transfection with DEC1 repressed the activity of a DEC2 promoter reporter by as much as 90%. The repression was observed with wild type DEC1 but not its DNA binding-defective mutants. Studies with deletion and site-directed mutants located, in the proximal promoter, an E-box motif that supported the DEC1-mediated repression. Disruption of this E-box markedly abolished the ability of the reporter to respond to DEC1. Our findings assign for DEC1 the first target gene that is regulated through direct DNA binding. DEC/STRA/SHARP proteins are highly identical in the DNA binding domain but much more diverse in other areas. DEC1-mediated repression on the expression of DEC2 provides an important mechanism that these transcription factors regulate the cellular function not only by modulating the expression of their target genes but also the expression of members within the same class.
DEC1 (differentially expressed in chondrocytes 1) and DEC2 are E-box-binding transcription factors and exhibit a circadian expression pattern. Recently, both proteins were found to repress the Clock/Bmal1-activated E-box promoters (e.g. mPer1). Yeast two-hybrid assay detected interactions between Bmal1 and DECs. It was hypothesized that DEC-mediated repression on the mPer1 promoter is achieved by binding to E-box elements and interacting with Bmal1. In the present study, we report that E-box binding rather than Bmal1 interaction is responsible for the observed repression. In the absence of Clock/Bmal1, both DEC1 and DEC2 markedly repressed the mPer1 promoter reporter; however, DNA-binding mutants showed no repressive activity. Similarly, DEC1, but not its DNA-binding mutants, repressed the Clock/Bmal1-induced activation. In addition, DEC1(R58P), a DNA-binding mutant with Bmal1 interactivity, repressed neither the mPer1 reporter directly nor the Clock/Bmal1-induced activation, providing direct evidence that DNA binding, rather than Bmal1 interactions, is responsible for the repression on the mPer1 promoter. Furthermore, disruption of the Sp1 site in the proximal promoter of mPer1 increased the repression of DEC1 proteins. Previous studies with mouse DEC2 showed that this factor interacts with Sp1. These findings suggest that DEC proteins regulate the expression of mPer1 through E-box binding and Sp1 interaction. Alterations on circadian systems are increasingly recognized as important risk factors for disease initiation and progression, and the expression of Dec genes is rapidly induced by environmental stimuli and is highly increased in tumour tissues. Therefore de-regulated expression of DEC genes probably alters normal circadian rhythms and contributes significantly to the pathogenesis of many diseases including cancer.
DEC1 suppresses CLOCK/BMAL1-enhanced promoter activity, but its role in the circadian system of mammals remains unclear. Here we examined the effect of Dec1 overexpression or deficiency on circadian gene expression triggered with 50% serum. Overexpression of Dec1 delayed the phase of clock genes such as Dec1, Dec2, Per1, and Dbp that contain E boxes in their regulatory regions, whereas it had little effect on the circadian phase of Per2 and Cry1 carrying CACGTT E' boxes. In contrast, Dec1 deficiency advanced the phase of the E-box-containing clock genes but not that of the E'-box-containing clock genes. Accordingly, DEC1 showed strong binding and transrepression on the E box, but not on the E' box, in chromatin immunoprecipitation, electrophoretic mobility shift, and luciferase reporter assays. Dec1-/- mice showed behavioral rhythms with slightly but significantly longer circadian periods under conditions of constant darkness and faster reentrainment to a 6-h phase-advanced shift of a light-dark cycle. Knockdown of Dec2 with small interfering RNA advanced the phase of Dec1 and Dbp expression, and double knockdown of Dec1 and Dec2 had much stronger effects on the expression of the E-box-containing clock genes. These findings suggest that DEC1, along with DEC2, plays a role in the finer regulation and robustness of the molecular clock.
RNA polymerase II distal enhancer sequence-specific DNA binding transcription factor activitydefinition[GO:0003705]
Interacting selectively and non-covalently with a sequence of DNA that is in a distal enhancer region for RNA polymerase II (RNAP II) in order to modulate transcription by RNAP II.
ISSOrtholog Curator
RNA polymerase II transcription factor binding transcription factor activity involved in negative regulation of transcriptiondefinition[GO:0001191]
Interacting selectively and non-covalently with an RNA polymerase II transcription factor, which may be a single protein or a complex, in order to stop, prevent, or reduce the frequency, rate or extent of transcription from an RNA polymerase II promoter. A protein binding transcription factor may or may not also interact with the template nucleic acid (either DNA or RNA) as well.
DEC1 suppresses CLOCK/BMAL1-enhanced promoter activity, but its role in the circadian system of mammals remains unclear. Here we examined the effect of Dec1 overexpression or deficiency on circadian gene expression triggered with 50% serum. Overexpression of Dec1 delayed the phase of clock genes such as Dec1, Dec2, Per1, and Dbp that contain E boxes in their regulatory regions, whereas it had little effect on the circadian phase of Per2 and Cry1 carrying CACGTT E' boxes. In contrast, Dec1 deficiency advanced the phase of the E-box-containing clock genes but not that of the E'-box-containing clock genes. Accordingly, DEC1 showed strong binding and transrepression on the E box, but not on the E' box, in chromatin immunoprecipitation, electrophoretic mobility shift, and luciferase reporter assays. Dec1-/- mice showed behavioral rhythms with slightly but significantly longer circadian periods under conditions of constant darkness and faster reentrainment to a 6-h phase-advanced shift of a light-dark cycle. Knockdown of Dec2 with small interfering RNA advanced the phase of Dec1 and Dbp expression, and double knockdown of Dec1 and Dec2 had much stronger effects on the expression of the E-box-containing clock genes. These findings suggest that DEC1, along with DEC2, plays a role in the finer regulation and robustness of the molecular clock.
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.
Sequence-specific DNA binding RNA polymerase II transcription factor activitydefinition[GO:0000981]
Interacting selectively and non-covalently with a specific DNA sequence in order to modulate transcription by RNA polymerase II. The transcription factor may or may not also interact selectively with a protein or macromolecular complex.
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.
Interacting selectively and non-covalently with a specific DNA sequence in order to modulate transcription. The transcription factor may or may not also interact selectively with a protein or macromolecular complex.
The differentiation of human embryo chondrocytes was markedly induced by the addition of Bt2cAMP to the culture medium. Using this culture system, a novel human cDNA for a basic helix-loop-helix (bHLH) protein (named DEC1) expressed primarily in the chondrocytes in response to Bt2cAMP was cloned by the subtractive hybridization method. DEC1 protein consists of 412 amino acids and exhibits structural similarities to the mammalian HES family, Drosophila hairy, and Enhancer of split m7 in the bHLH region. Northern blot analysis showed that DEC1 mRNA was expressed in various tissues including the cartilage, lung, spleen, and intestine, but not in the brain. These findings suggest that the bHLH factor DEC is involved in the control of cell differentiation in several tissues including cartilage.
Any process that modulates the frequency, rate or extent of gene expression such that an expression pattern recurs with a regularity of approximately 24 hours.
DEC1 suppresses CLOCK/BMAL1-enhanced promoter activity, but its role in the circadian system of mammals remains unclear. Here we examined the effect of Dec1 overexpression or deficiency on circadian gene expression triggered with 50% serum. Overexpression of Dec1 delayed the phase of clock genes such as Dec1, Dec2, Per1, and Dbp that contain E boxes in their regulatory regions, whereas it had little effect on the circadian phase of Per2 and Cry1 carrying CACGTT E' boxes. In contrast, Dec1 deficiency advanced the phase of the E-box-containing clock genes but not that of the E'-box-containing clock genes. Accordingly, DEC1 showed strong binding and transrepression on the E box, but not on the E' box, in chromatin immunoprecipitation, electrophoretic mobility shift, and luciferase reporter assays. Dec1-/- mice showed behavioral rhythms with slightly but significantly longer circadian periods under conditions of constant darkness and faster reentrainment to a 6-h phase-advanced shift of a light-dark cycle. Knockdown of Dec2 with small interfering RNA advanced the phase of Dec1 and Dbp expression, and double knockdown of Dec1 and Dec2 had much stronger effects on the expression of the E-box-containing clock genes. These findings suggest that DEC1, along with DEC2, plays a role in the finer regulation and robustness of the molecular clock.
DEC1 suppresses CLOCK/BMAL1-enhanced promoter activity, but its role in the circadian system of mammals remains unclear. Here we examined the effect of Dec1 overexpression or deficiency on circadian gene expression triggered with 50% serum. Overexpression of Dec1 delayed the phase of clock genes such as Dec1, Dec2, Per1, and Dbp that contain E boxes in their regulatory regions, whereas it had little effect on the circadian phase of Per2 and Cry1 carrying CACGTT E' boxes. In contrast, Dec1 deficiency advanced the phase of the E-box-containing clock genes but not that of the E'-box-containing clock genes. Accordingly, DEC1 showed strong binding and transrepression on the E box, but not on the E' box, in chromatin immunoprecipitation, electrophoretic mobility shift, and luciferase reporter assays. Dec1-/- mice showed behavioral rhythms with slightly but significantly longer circadian periods under conditions of constant darkness and faster reentrainment to a 6-h phase-advanced shift of a light-dark cycle. Knockdown of Dec2 with small interfering RNA advanced the phase of Dec1 and Dbp expression, and double knockdown of Dec1 and Dec2 had much stronger effects on the expression of the E-box-containing clock genes. These findings suggest that DEC1, along with DEC2, plays a role in the finer regulation and robustness of the molecular clock.
Negative regulation of sequence-specific DNA binding transcription factor activitydefinition[GO:0043433]
Any process that stops, prevents, or reduces the frequency, rate or extent of the activity of a transcription factor, any factor involved in the initiation or regulation of transcription.
DEC1 suppresses CLOCK/BMAL1-enhanced promoter activity, but its role in the circadian system of mammals remains unclear. Here we examined the effect of Dec1 overexpression or deficiency on circadian gene expression triggered with 50% serum. Overexpression of Dec1 delayed the phase of clock genes such as Dec1, Dec2, Per1, and Dbp that contain E boxes in their regulatory regions, whereas it had little effect on the circadian phase of Per2 and Cry1 carrying CACGTT E' boxes. In contrast, Dec1 deficiency advanced the phase of the E-box-containing clock genes but not that of the E'-box-containing clock genes. Accordingly, DEC1 showed strong binding and transrepression on the E box, but not on the E' box, in chromatin immunoprecipitation, electrophoretic mobility shift, and luciferase reporter assays. Dec1-/- mice showed behavioral rhythms with slightly but significantly longer circadian periods under conditions of constant darkness and faster reentrainment to a 6-h phase-advanced shift of a light-dark cycle. Knockdown of Dec2 with small interfering RNA advanced the phase of Dec1 and Dbp expression, and double knockdown of Dec1 and Dec2 had much stronger effects on the expression of the E-box-containing clock genes. These findings suggest that DEC1, along with DEC2, plays a role in the finer regulation and robustness of the molecular clock.
Human DEC (differentially expressed in chondrocytes), mouse STRA (stimulated with retinoic acid), and rat SHARP (split and hairy related protein) proteins constitute a new and structurally distinct class of the basic helix-loop-helix proteins. In each species, two members are identified with a sequence identity of >90% in the basic helix-loop-helix region and approximately 40% in the total proteins, respectively. Recently, we have reported that DEC1 is abundantly expressed in colon carcinomas but not in the adjacent normal tissues. The present study was undertaken to extend the expression study of DEC1 and to determine whether DEC1 and DEC2 had similar expression patterns among paired cancer-normal tissues from the colon, lung, and kidney. Without exceptions, DEC1 was markedly higher in the carcinomas, whereas the opposite was true with DEC2. In stable transfectants, tetracycline-induced expression of DEC1 caused proportional decreases in the expression of DEC2. Co-transfection with DEC1 repressed the activity of a DEC2 promoter reporter by as much as 90%. The repression was observed with wild type DEC1 but not its DNA binding-defective mutants. Studies with deletion and site-directed mutants located, in the proximal promoter, an E-box motif that supported the DEC1-mediated repression. Disruption of this E-box markedly abolished the ability of the reporter to respond to DEC1. Our findings assign for DEC1 the first target gene that is regulated through direct DNA binding. DEC/STRA/SHARP proteins are highly identical in the DNA binding domain but much more diverse in other areas. DEC1-mediated repression on the expression of DEC2 provides an important mechanism that these transcription factors regulate the cellular function not only by modulating the expression of their target genes but also the expression of members within the same class.
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.
DEC1 (differentially expressed in chondrocytes 1) and DEC2 are E-box-binding transcription factors and exhibit a circadian expression pattern. Recently, both proteins were found to repress the Clock/Bmal1-activated E-box promoters (e.g. mPer1). Yeast two-hybrid assay detected interactions between Bmal1 and DECs. It was hypothesized that DEC-mediated repression on the mPer1 promoter is achieved by binding to E-box elements and interacting with Bmal1. In the present study, we report that E-box binding rather than Bmal1 interaction is responsible for the observed repression. In the absence of Clock/Bmal1, both DEC1 and DEC2 markedly repressed the mPer1 promoter reporter; however, DNA-binding mutants showed no repressive activity. Similarly, DEC1, but not its DNA-binding mutants, repressed the Clock/Bmal1-induced activation. In addition, DEC1(R58P), a DNA-binding mutant with Bmal1 interactivity, repressed neither the mPer1 reporter directly nor the Clock/Bmal1-induced activation, providing direct evidence that DNA binding, rather than Bmal1 interactions, is responsible for the repression on the mPer1 promoter. Furthermore, disruption of the Sp1 site in the proximal promoter of mPer1 increased the repression of DEC1 proteins. Previous studies with mouse DEC2 showed that this factor interacts with Sp1. These findings suggest that DEC proteins regulate the expression of mPer1 through E-box binding and Sp1 interaction. Alterations on circadian systems are increasingly recognized as important risk factors for disease initiation and progression, and the expression of Dec genes is rapidly induced by environmental stimuli and is highly increased in tumour tissues. Therefore de-regulated expression of DEC genes probably alters normal circadian rhythms and contributes significantly to the pathogenesis of many diseases including cancer.
An autofeedback loop associated with transcription of clock gene(s), Per(s), is generally accepted as the molecular machinery of circadian rhythm generation, in which CLOCK/BMAL act as positive regulators and PER/CRY as negative ones. We show here an autofeedback loop of Dec1 encoding a basic helix-loop-helix transcription factor: CLOCK/BMAL increased the promoter activity of Dec1, and DEC1 and DEC2 as well as PERs and CRYs suppressed the induced expression. Three CACGTG E-boxes are responsible for both the activation and the suppression of Dec1 transcription. Forced expression of Clock/Bmal increased endogenous Dec1 mRNA level, and overexpression of Dec1 resulted in suppression of Dec2, Per2, and Dbp expression. The level of Dec1 expression in the heart of Clock/Clock mutant mice was continuously low throughout the day. These findings suggest that Dec1 is positively regulated by CLOCK/BMAL and is involved in circadian rhythm regulation by suppressing CLOCK/BMAL-induced gene expression. The autofeedback loop of Dec1 may be interlocked with the core feedback loop of Per in some situations.
The differentiation of human embryo chondrocytes was markedly induced by the addition of Bt2cAMP to the culture medium. Using this culture system, a novel human cDNA for a basic helix-loop-helix (bHLH) protein (named DEC1) expressed primarily in the chondrocytes in response to Bt2cAMP was cloned by the subtractive hybridization method. DEC1 protein consists of 412 amino acids and exhibits structural similarities to the mammalian HES family, Drosophila hairy, and Enhancer of split m7 in the bHLH region. Northern blot analysis showed that DEC1 mRNA was expressed in various tissues including the cartilage, lung, spleen, and intestine, but not in the brain. These findings suggest that the bHLH factor DEC is involved in the control of cell differentiation in several tissues including cartilage.
The synthesis of RNA from a DNA template by RNA polymerase II, originating at an RNA polymerase II promoter. Includes transcription of messenger RNA (mRNA) and certain small nuclear RNAs (snRNAs).
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.
Protein involved in the transfer of genetic information from DNA to messenger RNA (mRNA) by DNA-directed RNA polymerase. In the case of some RNA viruses, protein involved in the transfer of genetic information from RNA to messenger RNA (mRNA) by RNA-directed RNA polymerase.
A reference proteome is a set of protein sequences derived from a complete proteome which constitutes a defined standard for a particular user community. Reference proteomes are manually defined according to a number of criteria. They cover the proteomes of well- studied model organisms and other proteomes of interest for biomedical and biotechnological research. Reference proteomes have been selected to provide broad coverage of the tree of life, and constitute a representative cross-section of the taxonomic diversity to be found within UniProtKB.
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