Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.14.14.3 (luciferase)
 38,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The organic cation transporter-1 (OCT1) mediates the hepatocellular uptake of cationic drugs and endobiotics from sinusoidal blood. The uptake rates of these compounds may depend on OCT1 expression level. Because little is known about the regulation of the human OCT1 (hOCT1) gene, we characterized the hOCT1 promoter with respect to DNA-response elements and their binding factors. By computer analysis, we identified two adjacent putative DNA-response elements for the liver-enriched homodimeric nuclear receptor hepatocyte nuclear factor-4alpha (HNF-4alpha) in the hOCT1 promoter. Each element is of the direct repeat (DR)-2 format, containing directly repeated hexamers separated by two bases. In electrophoretic mobility shift assays, both elements directly interacted with HNF-4alpha. A luciferase reporter construct containing the hOCT1 promoter was strongly activated by HNF-4alpha in transiently transfected Huh7 cells. Site-directed mutagenesis of either DR-2 element alone or in combination severely decreased the HNF-4alpha-mediated activation of the hOCT1 promoter, indicating that both elements are functionally important. Because HNF-4alpha is a known target for bile acid-mediated suppression of transcription, we studied whether chenodeoxycholic acid (CDCA) suppresses hOCT1 gene expression by inhibiting HNF-4alpha-mediated transactivation. Treatment of cells with CDCA could indeed suppress the activation of the endogenous hOCT1 gene by HNF-4alpha. In addition, bile acid-inducible transcriptional repressor, small heterodimer partner (SHP), inhibited activation of the reporter-linked hOCT1 promoter and of the endogenous hOCT1 gene by HNF-4alpha. In conclusion, the hOCT1 gene, encoding an important drug transporter in the human liver, is activated by HNF-4alpha and suppressed by bile acids via SHP.
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PMID:The human organic cation transporter-1 gene is transactivated by hepatocyte nuclear factor-4alpha. 1643

Adipocyte enhancer binding protein 1 (AEBP1) is a transcriptional repressor of the aP2 gene, which encodes the adipocyte lipid binding protein and is involved in the differentiation of preadipocytes into mature adipocytes. It is an isoform of aortic carboxypeptidase-like protein (ACLP), which is a part of the extracellular matrix. AEBP1 and ACLP contain a conserved carboxypeptidase domain which is critical for the function of AEBP1 as a transcriptional repressor. Homology modeling and multiple alignment of AEBP1 homologues were performed to identify putative domains and critical residues that were then deleted or mutated in mouse AEBP1. Expression of wild-type and mutant AEBP1 proteins in CHO cells was performed, and their function in transcriptional repression was assayed by luciferase assay. All deletion forms of AEBP1 were able to repress transcription driven by the aP2 promoter. The DNA binding domain of AEBP1 was mapped by electrophoretic mobility shift assays to a region of the C-terminus rich in basic residues. However, wild-type AEBP1 was not able to interact strongly with DNA, suggesting that AEBP1 might function predominantly as a corepressor, independent of DNA binding. AEBP1 was also found to interact with Ca2+/calmodulin through this basic region, suggesting another mechanism of functional regulation.
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PMID:Modeling and functional analysis of AEBP1, a transcriptional repressor. 1653 15

The gene promoter of Drosophila proliferating cell nuclear antigen (dPCNA) contains several transcriptional regulatory elements, such as upstream regulatory element (URE), DNA replication-related element (DRE, 5'-TATCGATA), and E2F recognition sites. In the present study, a yeast one-hybrid screen using three tandem repeats of DRE in dPCNA promoter as the bait allowed isolation of a cDNA encoding Cut, a Drosophila homolog of mammalian CCAAT-displacement protein (CDP)/Cux. Electrophoretic mobility shift assays showed that Cut bound to both DRE and the sequence 5'-AATCAAAC in URE, with much higher affinity to the former. Measurement of dPCNA promoter activity by transient luciferase expression assays in Drosophila S2 cells after an RNA interference for Cut or DREF showed DREF activates the dPCNA promoter while Cut functions as a repressor. Chromatin immunoprecipitation assays in the presence or absence of 20-hydroxyecdysone further showed both DREF and Cut proteins to be localized in the genomic region containing the dPCNA promoter in S2 cells, especially in the Cut case upon induction of differentiation. These results indicate that Cut functions as a transcriptional repressor of dPCNA gene by binding to the promoter region in the differentiated state, while DREF binds to DRE to promote expression of dPCNA during cell proliferation.
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PMID:Antagonistic regulation of the Drosophila PCNA gene promoter by DREF and Cut. 1662 2

Calcitonin (CT), whose secretion from thyroid glands is regulated by increases in the concentration of extracellular Ca(2+), is a well-known hormone that regulates calcium homeostasis. However, the molecular mechanisms underlying the gene expression dependent on Ca(2+) have not been clarified. The downstream regulatory element (DRE) antagonist modulator (DREAM) was recently identified as a Ca(2+)-dependent transcriptional repressor. In the present study, we investigated the possible involvement of DREAM in the regulation of CT gene expression and secretion. A luciferase assay using TT cells, a thyroid carcinoma cell line, showed that a particular region in the CT gene promoter repressed the promoter activity under basal conditions but induced the activity when the Ca(2+) concentration was increased. We found two DRE sequences in a region located upstream from the transcription start site. Gel retardation assay confirmed that DREAM bound to the CT-DRE and also indicated that DREAM bound to the DRE in a Ca(2+)-dependent manner. We generated stable transfectants of TT cells with wild-type or mutant DREAM, which lacked the responsiveness to Ca(2+) changes. In contrast to the wild type, overexpression of the mutant DREAM inhibited the increase in CT secretion induced by a calcium ionophore. The addition of forskolin to increase cAMP activated the CT promoter, probably by the interaction of DREAM with cAMP-responsive element binding proteins, independent on the activation by Ca(2+). Together, these results suggest that DREAM plays an important role in human CT gene expression in a Ca(2+)- and cAMP-dependent manner.
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PMID:Ca2+-dependent regulation of calcitonin gene expression by the transcriptional repressor DREAM. 1684 May 49

Both cyclic AMP (cAMP) and nerve growth factor (NGF) have been shown to cause rapid activation of cAMP response element-binding protein (CREB) by phosphorylation of serine 133, but additional regulatory events contribute to CREB-targeted gene expression. Here, we have used stable transfection with a simple cAMP response element (CRE)-driven reporter to address the kinetics of CRE-dependent transcription during neuronal differentiation of PC12 cells. In naive cells, dibutyryl cAMP (dbcAMP) generated a rapid increase in CRE-driven luciferase activity by 5 h that returned to naive levels by 24 h. Luciferase induction after NGF treatment was delayed until 48 h when CRE-driven luciferase expression became TrkA dependent. Blocking histone deacetylase (HDAC) activity accelerated NGF-dependent CRE-driven luciferase expression by at least 24 h and resulted in a sustained cAMP-dependent expression of CRE-driven luciferase beyond 24 h. Inhibition of protein synthesis before stimulation with NGF or dbcAMP indicated that both stimuli induce expression of a transcriptional repressor that delays NGF-dependent and attenuates cAMP-dependent CRE-driven transcription. NGF caused a rapid but transient HDAC-dependent increase in inducible cAMP element repressor (ICER) expression, but ICER expression was sustained with increased cAMP. Depletion of ICER from PC12 cells indicated that HDAC-dependent ICER induction is responsible for the delay in CRE-dependent transcription after NGF treatment.
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PMID:PC12 cells regulate inducible cyclic AMP (cAMP) element repressor expression to differentially control cAMP response element-dependent transcription in response to nerve growth factor and cAMP. 1705 58

Activation of c-fos in brain is related to coupling of neuronal activity to gene expression, but also to pathological conditions such as seizures or excitotoxicity-induced cell death. Glutamate activates c-fos in neurons through the calcium-dependent phosphorylation of CREB by ERK and/or CaMKIV kinase pathways downstream NMDA-receptors. In glial cells, however, the activation of c-fos by glutamate is poorly understood. Because glial cells actively modulate neuronal excitability and the brain's response to injury, we studied the mechanisms by which glutamate activates c-fos in rat cortical glial cells. Glutamate potently induced c-fos mRNA in a calcium-dependent manner, as demonstrated by using the calcium chelator BAPTA-AM. Glutamate-induced c-fos mRNA expression was not sensitive to inhibitors of ERK, p38(MAPK), or CaMK pathways, indicating that glial c-fos is activated by a distinct mechanism. Thapsigargin abolished the glutamate effect on c-fos mRNA, indicating ER calcium mobilization. Additionally, glutamate induction of c-fos mRNA was sensitive to the mGluR5 antagonist MPEP but not the NMDA-R antagonist MK-801. In luciferase reporter assays, DRE, which actively represses c-fos by binding the calcium-binding transcriptional repressor DREAM, was activated by glutamate, whereas SRE and CRE were not. Finally, glutamate caused the nuclear export of DREAM in astrocytes, and transfection of astrocytes with a mutant variant of DREAM that constitutively binds DNA inhibited glutamate-induced c-Fos expression. These findings are in sharp contrast to the mechanism described in neurons and suggest a novel pathway activated by glutamate in glial cells that employs mGluR5, ER calcium, and the derepression of c-fos at the DRE.
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PMID:Glutamate activates c-fos in glial cells via a novel mechanism involving the glutamate receptor subtype mGlu5 and the transcriptional repressor DREAM. 1712 Feb 44

Bcl6, a sequence-specific transcriptional repressor, is important for generation and maintenance of memory CD8(+) T cells. Although memory CD8(+) T cells are generated from effector CD8(+) T cells, a role for Bcl6 in effector CD8(+) T cells is largely unknown. We show here that Bcl6 expression was transiently induced in activated CD8(+) T cells and continuously up-regulated in effector CD8(+) T cells. The amount of granzyme B mRNA among effector molecules produced by effector CD8(+) T cells inversely correlated with the amount of Bcl6 mRNA in CD8(+) T cells. Overexpression of Bcl6 in CD8(+) T cells resulted in lower killing activity at their effector phase, supporting the reduction of granzyme B expression in effector CD8(+) T cells by Bcl6. We identified a putative Bcl6-binding DNA sequence in the promoter region of the granzyme B gene. Binding of Bcl6 to the Bcl6-binding sequence was detected in naive CD8(+) T cells but not in activated CD8(+) T cells by chromatin immunoprecipitation assay. Furthermore, the Bcl6-binding sequence was required for Bcl6 to repress the luciferase reporter gene expression controlled by the granzyme B promoter. Thus, the granzyme B gene is a molecular target of Bcl6 in effector CD8(+) T cells.
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PMID:Bcl6 controls granzyme B expression in effector CD8+ T cells. 1712 45

Myeloid Elf-1 like factor (MEF) is a member of the Ets transcription factor family. Ets family proteins control the expression of genes that are critical for biological processes such as proliferation, differentiation, and cell death. Some of Ets factors are also known to regulate bone development. In this study, we investigated the role of MEF in osteoblast differentiation. MEF expression was highest early in the differentiation of MC3T3-E1 osteoblasts and was reduced by treatment with BMP-2. The expression of MEF suppressed the alkaline phosphatase activity and expression induced by BMP-2 stimulation and mediated by Runx2. The expression of MEF also reduces osteocalcin mRNA levels, and mineralization in MC3T3-E1 cells. We found that the MEF-mediated suppression of osteogenic differentiation was critically related to Runx2 regulation. The MEF and Runx2 proteins physically interact to form a complex, and this interaction interferes with Runx2 binding to the cis-acting element OSE2 derived from the osteocalcin promoter. Co-transfection of MEF inhibited the 6xOSE2-luciferase reporter activity induced by Runx2. In addition, MEF stimulated the transcription of a negative mediator Msx2, and a transcriptional repressor, Mab21L1, and suppressed the transcription of a positive mediator, Dlx5 in osteoblast differentiation. MEF overexpression stimulated C2C12 cell proliferation. Together, our findings suggest that MEF promotes cell proliferation and functions as a negative regulator of osteogenic differentiation by directly interacting with Runx2 and suppressing its transcriptional activity.
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PMID:The suppressive effect of myeloid Elf-1-like factor (MEF) in osteogenic differentiation. 1716 70

A transcription corepressor, MAT1-mediated transcriptional repressor (MMTR), was found in mouse embryonic stem cell lines. MMTR orthologs (DMAP1) are found in a wide variety of life forms from yeasts to humans. MMTR down-regulation in differentiating mouse embryonic stem cells in vitro resulted in activation of many unrelated genes, suggesting its role as a general transcriptional repressor. In luciferase reporter assays, the transcriptional repression activity resided at amino acids 221 to 468. Histone deacetylase 1 (HDAC1) interacts with MMTR both in vitro and in vivo and also interacts with MMTR in the nucleus. Interestingly, MMTR activity was only partially rescued by competition with dominant-negative HDAC1(H141A) or by treatment with an HDAC inhibitor, trichostatin A (TSA). To identify the protein responsible for HDAC1-independent MMTR activity, we performed a yeast two-hybrid screen with the full-length MMTR coding sequence as bait and found MAT1. MAT1 is an assembly/targeting factor for cyclin-dependent kinase-activating kinase which constitutes a subcomplex of TFIIH. The coiled-coil domain in the middle of MAT1 was confirmed to interact with the C-terminal half of MMTR, and the MMTR-mediated transcriptional repression activity was completely restored by MAT1 in the presence of TSA. Moreover, intact MMTR was required to inhibit phosphorylation of the C-terminal domain in the RNA polymerase II largest subunit by TFIIH kinase in vitro. Taken together, these data strongly suggest that MMTR is part of the basic cellular machinery for a wide range of transcriptional regulation via interaction with TFIIH and HDAC.
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PMID:Corepressor MMTR/DMAP1 is involved in both histone deacetylase 1- and TFIIH-mediated transcriptional repression. 1737 48

Loss of function mutations in SALL4 cause Okihiro syndrome, an autosomal dominant disorder characterised by radial ray malformations associated with Duane anomaly. In zebrafish and mouse Sall4 interacts with TBX5 during limb and heart development and plays a crucial role for embryonic stem (ES) cell pluripotency. Here we report the nuclear interaction of murine Sall4 with Cyclin D1, one of the main regulators of G(1) to S phase transition in cell cycle, verified by yeast two-hybrid assay, co-immunoprecipitation and intracellular co-localisation. Furthermore, using luciferase reporter gene assays we demonstrate that Sall4 operates as a transcriptional repressor located to heterochromatin and that this activity is modulated by Cyclin D1.
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PMID:Synergistic cooperation of Sall4 and Cyclin D1 in transcriptional repression. 1738 11


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