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Results for “regulatory module”

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At least 271 records · Page 15Linked to original sources

PubMed1999

Recognition of NFATp/AP-1 composite elements within genes induced upon the activation of immune cells.

Composite elements are regulatory modules of promoters or enhancers that consist of binding sites of two different but synergizing transcription factors. A well-studied example is nuclear factors of activated T-cell (NFAT) sites which are composite elements of a NFATp/c and an activating protein 1 (AP-1) binding site. We have developed a computational approach to identify potential NFAT target genes which (a) comprises an improved method to scan for individual NFAT composite elements; (b) considers positional effects relative to transcription start sites; and (c) involves cluster analysis of potential NFAT composite elements. All three steps progressively helpX?ed to discriminate T-cell-specific promoter sequences against other functional regions (coding and intronic sequences) of the same genes, against promoters of muscle-specific genes or against random sequences. Using this approach, we identified potential NFAT composite elements in promoters of cytokine genes and their receptors as well as in promoters of genes for AP-1 family members, Ca2+-binding proteins and some other components of the regulatory network operating in activated T-cells and other immune cells. The method developed can be adapted to characterize and identify other composite elements as well. The program for recognition NFAT composite elements is available through the World Wide Web (http://compel.bionet.nsc.ru/FunSite/CompelScan. html and http://transfac.gbf.de/dbsearch/funsitep/s _comp.html).

Animals↗

PubMed1997

T-cell proto-oncogene rhombotin-2 is a complex transcription regulator containing multiple activation and repression domains.

The LIM domain protein rhombotin-2 (RBTN-2/TTG-2/LMO2) is involved in many processes, including leukemogenesis and erythropoiesis. It is thought that the principle role of RBTN-2 in these processes is to regulate transcription. To examine the potential for RBTN-2 to modulate transcription, we constructed RBTN-2/GAL4 DNA-binding domain fusion proteins and measured their ability to activate transcription of a reporter gene construct. From these studies we identified a transcription activation domain within the NH2 terminus of RBTN-2. This activation domain was further localized within a proline-rich 19-amino acid region. A second activation domain of 11 amino acids was also identified. This domain was located within the COOH terminus of RBTN-2, and functioned in mammalian cells but not in yeast. Furthermore, the two LIM domains of RBTN-2 were shown to function as transcription repression domains. Each individual LIM domain acted as an independent transcription repression domain on a heterologous activation domain. However, in context of full-length RBTN-2, the LIM domains selectively repressed the NH2-terminal activation domain, but had no effect on the COOH-terminal domain. Overall, these results demonstrate that the T-cell oncogene RBTN-2 is a complex transcription factor possessing multiple transcription regulatory modules, including two activation domains and two repression domains.

Animals↗

PubMed2000

Evidence for stabilizing selection in a eukaryotic enhancer element.

Eukaryotic gene expression is mediated by compact cis-regulatory modules, or enhancers, which are bound by specific sets of transcription factors. The combinatorial interaction of these bound transcription factors determines time- and tissue-specific gene activation or repression. The even-skipped stripe 2 element controls the expression of the second transverse stripe of even-skipped messenger RNA in Drosophila melanogaster embryos, and is one of the best characterized eukaryotic enhancers. Although even-skipped stripe 2 expression is strongly conserved in Drosophila, the stripe 2 element itself has undergone considerable evolutionary change in its binding-site sequences and the spacing between them. We have investigated this apparent contradiction, and here we show that two chimaeric enhancers, constructed by swapping the 5' and 3' halves of the native stripe 2 elements of two species, no longer drive expression of a reporter gene in the wildtype pattern. Sequence differences between species have functional consequences, therefore, but they are masked by other co-evolved differences. On the basis of these results, we present a model for the evolution of eukaryotic regulatory sequences.

Animals↗

PubMed2006

MoD Tools: regulatory motif discovery in nucleotide sequences from co-regulated or homologous genes.

Understanding the complex mechanisms regulating gene expression at the transcriptional and post-transcriptional levels is one of the greatest challenges of the post-genomic era. The MoD (MOtif Discovery) Tools web server comprises a set of tools for the discovery of novel conserved sequence and structure motifs in nucleotide sequences, motifs that in turn are good candidates for regulatory activity. The server includes the following programs: Weeder, for the discovery of conserved transcription factor binding sites (TFBSs) in nucleotide sequences from co-regulated genes; WeederH, for the discovery of conserved TFBSs and distal regulatory modules in sequences from homologous genes; RNAProfile, for the discovery of conserved secondary structure motifs in unaligned RNA sequences whose secondary structure is not known. In this way, a given gene can be compared with other co-regulated genes or with its homologs, or its mRNA can be analyzed for conserved motifs regulating its post-transcriptional fate. The web server thus provides researchers with different strategies and methods to investigate the regulation of gene expression, at both the transcriptional and post-transcriptional levels. Available at http://www.pesolelab.it/modtools/ and http://www.beacon.unimi.it/modtools/.

Binding Sites↗

PubMed2006

Effects of enamel matrix derivative on bone-related mRNA expression in human periodontal ligament cells in vitro.

BACKGROUND: Enamel matrix derivative (EMD) has demonstrated the potential to stimulate periodontal regeneration with mineralized tissue formation. Molecular regulators of bone metabolism include osteoprotegrin (OPG), receptor activator of nuclear factor kappa B ligand (RANKL), cyclooxygenase 2 (COX2), and core binding factor alpha 1 (Cbfa1). The role of these regulatory molecules within the context of EMD stimulation of mineralized tissue formation is unknown. Therefore, the purpose of this investigation was to explore the effects of EMD on these bone-related molecules in human periodontal ligament (PDL) cells. METHODS: Human PDL-cell cultures were treated with EMD (5 to 100 microg/ml) for 24 hours. Total RNA was isolated using phenolchloroform, and reverse transcription-polymerase chain reaction (RT-PCR) was performed using primers specific for OPG, RANKL, COX2, Cbfa1, and aldolase, with amplification in the exponential range for each molecule studied. RESULTS: The results of this study show that there is a significant (P <0.05) increase in COX2 mRNA levels with EMD treatment, and no effects were noted on mRNA levels for Cbfa1. RANKL mRNA levels were significantly decreased (P <0.01) up to 50% with EMD treatment > or =25 microg/ml. OPG levels showed minimal effects with EMD treatment. However, the RANKL/OPG ratio showed a 40% to 55% reduction with EMD >or =25 microg/ml. CONCLUSION: This study supports a role for EMD stimulation of mineralized tissue formation consistent with periodontal regeneration by modulating regulatory molecules critical to bone metabolism at the RNA level.

Adolescent↗

PubMed2026

Uncovering molecular regulatory networks of low-temperature stress response in Trachinotus ovatus via integrated transcriptome and metabolome analyses.

Golden pompano (Trachinotus ovatus) is one of the most economically important marine fish species in China. It is susceptible to low-temperature stress, which significantly challenges its production and supply. Nevertheless, study on the regulatory mechanisms underlying low-temperature stress responses in golden pompano remains limited. Here, we firstly performed a time-series transcriptome analysis to reconstruct dynamic response patterns under low-temperature stress in golden pompano. Transcriptome profiling identified common differentially expressed genes (DEGs), including fos, hlf, and hmgb1, as well as condition-specific DEGs across distinct low-temperature stress groups. Based on cluster analysis, all DEGs were classified into five distinct expression patterns, reflecting diversified regulation of expression in golden pompano during low-temperature stress. Furthermore, condition-specific regulatory modules were explored via weighted gene co-expression network analysis (WGCNA), highlighting that the two module hub genes, serbf2 and lipc, might respond to low-temperature stress by regulating the lipid catabolic process. Subsequently, untargeted metabolomic analysis revealed that glycerophospholipid metabolism was a significantly enriched common pathway, highlighting its crucial role in mediating the response to low-temperature stress. Finally, by integrating transcriptomic and metabolomic analyses, a gene-metabolite interaction network associated with glycerophospholipid metabolism under low-temperature stress was established. These findings underscore the significance of multiple candidate genes and glycerophospholipid metabolism in golden pompano's response to low-temperature stress, thereby laying a solid molecular foundation for the development of low-temperature-tolerant fish strains.

Animals↗

PubMed1997

Systemic modulation of peripheral eosinophilia (air pouch model) in Schistosoma mansoni infection.

Schistosoma mansoni infection induces in their hosts a marked and sustained eosinophilia, which is influenced or modulated by complex mechanisms, that vary according to the phase of infection. To address this phenomenon, we used the air pouch (AP) model in control and infected Swiss webster mice, analyzing the cellular, tissue response and local expression of adhesion molecules [CD18 (beta(2)-chain), CD44, ICAm-1 (CD54), L-selectin (CD62L), CD49d (alpha(4)-chain), LFA1 (CD11 alpha)]. Infected animals were studied at 3 (pre-oviposition phase), 7 (acute phase), and 14 (chronic phase) weeks after infection (5-6 mice/period of infection). Normal mice were age-matched. Results showed that after egg stimulation, compared with matched controls, the infected mice, at each point of infection, showed a lower eosinophil response in the acute (7 weeks) and chronic phase (14 weeks) of infection. However, when the infected mice were in pre-oviposition phase (3 weeks) their eosinophil response surpassed the control ones. In the AP wall of infected mice, a significant decrease in the expression of ICAM-1 and CD44 in fibroblastic-like cells and a reduction in the number of CD18 and CD11 alpha in migratory cells were observed. The other adhesion molecules were negative or weakly expressed. The results indicated that in the air pouch model, in S. mansoni-infected mice: (1) eosinophil response is strikingly down-regulated, during the acute ovular phase; (2) in the pre-oviposition phase, in contrast, it occurs an up-regulatory modulation of eosinophil response, in which the mechanisms are completely unknown; (3) in the chronic phase of the infection, the down modulation of eosinophil response is less pronounced; 4) Down-regulation of adhesion molecules, specially of ICAM-1 appear to be associated with the lower eosinophil response.

Animals↗

PubMed2006

cis-Regulatory sequences of the genes involved in apoptosis, cell growth, and proliferation may provide a target for some of the effects of acute ethanol exposure.

The physiological effects of alcohol are known to include drunkenness, toxicity, and addiction leading to alcohol-related health and societal problems. Some of these effects are mediated by regulation of expression of many genes involved in alcohol response pathways. Analysis of the regulatory elements and biological interaction of the genes that show coexpression in response to alcohol may give an insight into how they are regulated. Fifty-two ethanol-responsive (ER) genes displaying differential expression in mouse brain in response to acute ethanol exposure were subjected to bioinformatics analysis to identify known or putative transcription factor binding sites and cis-regulatory modules in the promoter regions that may be involved in their responsiveness to alcohol. Functional interactions of these genes were also examined to assess their cumulative contribution to metabolomic pathways. Clustering and promoter sequence analysis of the ER genes revealed the DNA binding site for nuclear transcription factor Y (NFY) as the most significant. NFY also take part in the proposed biological association network of a number of ER genes, where these genes interact with themselves and other cellular components, and may generate a major cumulative effect on apoptosis, cell survival, and proliferation in response to alcohol. NFY has the potential to play a critical role in mediating the expression of a set of ER genes whose interactions contribute to apoptosis, cell survival, and proliferation, which in turn may affect alcohol-related behaviors.

Animals↗

PubMed2000

The X1 box of HLA-G promoter is a target site for RFX and Sp1 factors.

HLA-G gene regulation was investigated with regards to homologies among the pathways regulating both classical MHC class I and MHC class II gene expression. They include four conserved cis-acting regulatory elements located in the proximal promoter region referred to as the W/S/Z box, the X box that is comprised of the X1 and X2 halves, and the Y box with an inverted CCAAT site. The X1 box is the binding site for the ubiquitous RFX complex consisting of three subunits; the X2 box is bound by the X2BP/ATF/CREB family factors. The basic S-X-Y regulatory module interacts with CIITA, which is expressed constitutively in APCs, but may be inducible in others cell types by IFN-gamma. Within HLA-G gene promoter the only conserved motifs are S and X1 boxes. We thus investigated the binding capacity of the HLA-G X box in comparison to that of HLA-DRA and HLA-E. We demonstrate that X2 box mutations in HLA-G promoter affect the binding of ATF/CREB family factors and may privilege the X2 box to access by other shared factors. The X1 box is the target for RFX complex and an additional factor we identified as Sp1. We propose that the X region in the HLA-G gene promoter might participate to the combination of factors which play a role in HLA-G gene activation.

Cell Extracts↗

PubMed2002

A novel TCTG(G/C) direct repeat and an A/T-rich HMG2-binding site control the expression of the rat cardiac troponin T gene.

We previously showed that the rat cardiac troponin T proximal promoter (-497bp from the transcriptional start site) was sufficient to confer cardiac-specific expression of a reporter gene in both cultured cardiomyocytes and transgenic mice. This promoter consists of two cis-regulatory modules with high sequence similarity. Nucleotides from -319 to -289 (termed D2) and nucleotides from -249 to -209 (termed F41) contain a TCTG(G/C) direct repeat and an A/T-rich sequence. Competition gel mobility shift assays revealed that the same protein factors were bound to both D2 and F41. Deletion and religation studies of the promoter suggested that D2 acted as an enhancer but could not totally substitute for the F41 function. Mutational analyses demonstrated that the direct repeat was required for the DNA-binding and promoter activity. Moreover, cardiac-specific 42kDa proteins and a ubiquitous high mobility group 2 (HMG2) protein were identified to be responsible for the binding to the TCTG(G/C) direct repeat and the A/T-rich sequence, respectively. Overexpression of HMG2 had differential effects on the promoter in cardiomyocytes versus fibroblasts. Our results provided the first evidence to support that HMG2 together with tissue-specific factors could direct a stimulatory or inhibitory effect on thecardiac troponin T gene expression in heart or non-heart tissue, respectively.

AT Rich Sequence↗

PubMedDate not supplied

Sarcoglycans in muscular dystrophy.

Muscular dystrophy is a heterogeneous genetic disease that affects skeletal and cardiac muscle. The genetic defects associated with muscular dystrophy include mutations in dystrophin and its associated glycoproteins, the sarcoglycans. Furthermore, defects in dystrophin have been shown to cause a disruption of the normal expression and localization of the sarcoglycan complex. Thus, abnormalities of sarcoglycan are a common molecular feature in a number of dystrophies. By combining biochemistry, molecular cell biology, and human and mouse genetics, a growing understanding of the sarcoglycan complex is emerging. Sarcoglycan appears to be an important, independent mediator of dystrophic pathology in both skeletal muscle and heart. The absence of sarcoglycan leads to alterations of membrane permeability and apoptosis, two shared features of a number of dystrophies. beta-sarcoglycan and delta-sarcoglycan may form the core of the sarcoglycan subcomplex with alpha- and gamma-sarcoglycan less tightly associated to this core. The relationship of epsilon-sarcoglycan to the dystrophin-glycoprotein complex remains unclear. Animals lacking alpha-, gamma- and delta-sarcoglycan have been described and provide excellent opportunities for further investigation of the function of sarcoglycan. Dystrophin with dystroglycan and laminin may be a mechanical link between the actin cytoskeleton and the extracellular matrix. By positioning itself in close proximity to dystrophin and dystroglycan, sarcoglycan may function to couple mechanical and chemical signals in striated muscle. Sarcoglycan may be an independent signaling or regulatory module whose position in the membrane is determined by dystrophin but whose function is carried out independent of the dystrophin-dystroglycan-laminin axis.

Amino Acid Sequence↗

PubMed2004

Identification of neuron-specific promoters in Ciona intestinalis.

We isolated 5' flanking regions of four genes, Ci-Galphai1, Ci-arr, Ci-vAChTP, and Ci-vGAT, each of which is expressed in distinct sets of neurons in the central nervous system of the ascidian Ciona intestinalis, and we examined their function by introducing green fluorescent protein (GFP)-fusion constructs into Ciona embryos. The reporter gene driven by the 5' flanking region of Ci-Galphai1, Ci-arr, and Ci-vAChTP recapitulated the endogenous gene expression patterns, while that of Ci-vGAT can drive GFP expression in particular subsets of neurons expressing the endogenous gene. Deletion analysis revealed that the Ci-Galphai1 promoter consists of multiple regulatory modules controlling the expression in different types of cells. The GFP fluorescence enabled visualization of cell bodies and axons of different sets of neurons in ascidian larvae. These promoters can be a powerful tool for studying molecular mechanisms of neuronal development as well as neuron networks and functions in ascidians.

Amino Acid Sequence↗

PubMed2006

A promoter element of the CD-RAP gene is required for repression of gene expression in non-cartilage tissues in vitro and in vivo.

The cartilage-derived retinoic acid-sensitive protein (CD-RAP) gene is expressed predominately in cartilage. Previous studies in transgenic mice have shown that the DNA promoter segment from -2,251 bp to -2,068 bp of the CD-RAP gene contains elements critical for gene expression. Subsequent studies revealed both positive and negative regulatory motifs in this 183 bp element. Here we show that this element demonstrates activation or repression of gene expression in vitro and in vivo based on cell type and content of transcription factors. The distribution of Sox (positive) and C/EBP (negative) transcription factors in cell lines and in mouse tissues is consistent with their positive and negative roles. In transgenic mice, when the 183-bp element was removed from a 3,345-bp cartilage-specific CD-RAP promoter, expression of the reporter gene became widespread, being observed in muscle, bone, lung, and liver in addition to cartilage. In vitro, mutation of the C/EBP site activated the inactive 3,345-bp CD-RAP gene promoter in myoblastic cells, suggesting that this site is responsible for (-2,079 bp) repression. These results indicate that the 183-bp element plays an important role in cartilage-specific gene expression by acting as a chondrocyte-regulatory module repressing transcription in non-chondrocytes and contributing to activation in chondrocytes. This is the first report of a functional DNA element necessary for repression in non-cartilage tissues in vivo.

Animals↗

PubMed1995

ATP bimodal switch that regulates the ligand binding and signal transduction activities of the atrial natriuretic factor receptor guanylate cyclase.

Atrial natriuretic factor (ANF)-dependent guanylate cyclase (ANF-RGC) is a single-chain transmembrane-spanning protein, containing both ANF binding and catalytic cyclase activity. ANF binding to the extracellular receptor domain activates the cytosolic catalytic domain, generating the second messenger cyclic GMP. Obligatory in this activation process is an intervening step regulated by the ATP binding to the cyclase. This is a signal transduction step that bridges the events of ligand binding and cyclase activation. A defined structural motif (Gly503-Xa-Gly505-Xa-Xa-Xa-Gly509), termed ATP regulatory module (ARM), is critical for this step. The present study shows that the ARM-Gly505 residue acts as an ATP bimodal switch in regulating both the ligand binding and signal transduction activities of ANF-RGC, thus representing a critical site to turn the hormone signal on and off.

Adenosine Triphosphate↗

PubMed1998

Chromosomal localization and immunological analysis of a family of human 26S proteasomal ATPases.

The 26S proteasome is a eukaryotic ATP-dependent protease functioning as a protein death machine. It is a large multisubunit complex, consisting of a catalytic 20S proteasome and two regulatory modules, named PA700. The PA700 complex is composed of multiple subunits of 25-110 kDa, which are classified into two subgroups, a subgroup of at least 6 ATPases that consitute a unique multi-gene family encoding homologous polypeptides conserved during evolution and a subgroup of approximately 15 non-ATPase subunits, most of which are structurally unrelated to each other. In the present study, we report the chromosomal localization and immunological properties of six members of the human 26S proteasomal ATPase family. By use of the fluorescence in situ hybridization method, the S4 (PSMC1), MSS1 (PSMC2), TBP1 (PSMC3), TBP7 (PSMC4), p45 (PSMC5), and p42 (PSMC6) genes were mapped to human chromosomes 19p13.3, 7q22.1-q22.3, 11p11.2, 19q13.11-q13.13, 17q23.1-q23.3, and 12q15, respectively, indicating that the genes for multiple ATPases of the 26S proteasome are located on different chromosomes. Immunoblot analysis revealed that all these ATPases were associated with the purified 26S proteasome and that some of them showed striking heterogeneity in their electrical charges.

Adenosine Triphosphatases↗

PubMed1998

Molecular biology of the proteasome.

The proteasome is an unusually large multisubunit proteolytic complex, consisting of a central catalytic machine (equivalent to the 20S proteasome) and two terminal regulatory subcomplexes, termed PA700 or PA28, that are attached to both ends of the central portion in opposite orientations to form the enzymatically active proteasome. Totally about 40 subunits with sizes of 20-110 kDa are assembled to form two types of the proteasomal complexes with the same catalytic core and different regulatory modules. To date, cDNAs or genes encoding almost all subunits of human and the budding yeast proteasomes have been isolated by molecular-biological techniques. In this minireview, I summarize briefly available information on the structure-function relationships of the proteasome acting as a protein death machinery.

Adenosine Triphosphatases↗

PubMed2000

An Nkx-dependent enhancer regulates cGATA-6 gene expression during early stages of heart development.

The evolutionarily conserved GATA-6 transcription factor is an early and persistent marker of heart development in diverse vertebrate species. We previously found evidence for a functionally conserved heart-specific enhancer upstream of the chicken GATA-6 (cGATA-6) gene and in the present study we used transgenic mouse assays to further characterize this regulatory module. We show that this enhancer is activated in committed precursor cells within the cardiac crescent and that it remains active in essentially all cardiogenic cells through the linear heart stage. Although this enhancer can account for cGATA-6 gene expression early in the cardiogenic program, it is not able to maintain expression throughout the heart later in development. In particular, the enhancer is sequentially downregulated along the posterior to anterior axis, with activity becoming confined to outflow tract myocardium. Enhancers with similar properties have been shown to regulate the early heart-restricted expression of the mouse Nkx2.5 transcription factor gene. Whereas these Nkx2.5 enhancers are GATA-dependent, we show that the cGATA-6 enhancer is Nkx-dependent. We speculate that these enhancers are silenced to allow GATA-6 and Nkx2.5 gene expression to be governed by region-specific enhancers in the multichambered heart.

Animals↗

PubMed1999

The murine Bin1 gene functions early in myogenesis and defines a new region of synteny between mouse chromosome 18 and human chromosome 2.

We cloned and functionally characterized the murine Bin1 gene as a first step to investigate its physiological roles in differentiation, apoptosis, and tumorigenesis. The exon-intron organization of the >/=55-kb gene is similar to that of the human gene. Consistent with a role for Bin1 in apoptosis, the promoter included a functional consensus motif for activation by NF-kappaB, an important regulator of cell death. A muscle regulatory module defined in the human promoter that includes a consensus recognition site for myoD family proteins was not conserved in the mouse promoter. However, Bin1 is upregulated in embryonic development by E10.5 in myotomes, the progenitors of skeletal muscle, supporting a role in myogenesis and suggesting that the mouse and human genes may be controlled somewhat differently during development. In C2C12 myoblasts antisense Bin1 prevents induction of the cell cycle kinase inhibitor p21WAF1, suggesting that it acts at an early time during the muscle differentiation program. Interspecific mouse backcross mapping located the Bin1 locus between Mep1b and Apc on chromosome 18. Since the human gene was mapped previously to chromosome 2q14, the location of Bin1 defines a previously unrecognized region of synteny between human chromosome 2 and mouse chromosome 18.

Adaptor Proteins, Signal Transducing↗