Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

HBP-1 is a sequence-specific DNA-binding protein that interacts with the hexameric sequence ACGTCA, the putative cis-acting element of the wheat histone H3 gene. Gel mobility shift and DNase I footprint analyses showed that this protein interacts with homologous sequences in the regulatory regions for the transcription of the cauliflower mosaic virus (CaMV) 35S RNA and nopaline synthase (NOS) genes, evidence that HBP-1 may bind to hexameric sequences in the regulatory regions of various genes. An HBP-1-like protein, indistinguishable from wheat HBP-1 in its the DNA-binding specificity, is present in sunflower nuclear extract, an indication that HBP-1-like DNA-binding proteins also exist in dicots.
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PMID:Wheat nuclear protein HBP-1 binds to the hexameric sequence in the promoter of various plant genes. 260 42

A nuclear protein(s), HBP-2, that binds to the upstream region of the wheat histone H4 gene was identified from a fractionated nuclear extract of wheat germ by DNase I footprinting. The DNase I-protected region contained the conserved nonameric motif, CATCCAACG. Cross-competition experiments that used the mobility shift assay showed that this nuclear protein(s) binds specifically to the upstream sequence that has been postulated to be a cis element of the wheat H3 gene. Our findings suggest that this DNA-binding protein(s) may be a trans-acting factor in the regulation of the transcription of wheat histone genes.
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PMID:DNA-binding protein(s) interacts with a conserved nonameric sequence in the upstream regions of wheat histone genes. 318 34

A nuclear extract from petioles of sweet potato protected several sites in the 5'-upstream region of a gene for beta-amylase from DNase I digestion. One of these sites, located at a region around 800-base pairs upstream from the transcription start site, having an imperfect palindromic sequence of CGTCACGTCACG, was designated the R-box. The site contained tandemly duplicated CGTCA sequences, referred to below as 5'- and 3'-CGTCA. Competition experiments in gel mobility shift assays with mutant R-box oligonucleotides indicated that mutations in bases outside the 3'-CGTCA of the R-box do not severely affect the binding. By contrast, single-base substitutions in any one base of the 3'-CGTCA greatly abolished the binding even when the mutated R-boxes contained intact 5'-CGTCA. However, oligonucleotides with mutations in the 3'-CGTCA had the ability to bind the nuclear factor when additional mutations were introduced to create a partially palindromic sequence containing the CGTCA sequence in its 3'-half on the opposite strand. These results indicate that the CGTCA sequence alone is not sufficient for the binding of the R-box binding factor (RBF) and that the RBF binds to the sequence with partial dyad symmetry that contains the CGTCA motif in its 3'-half. The optimum sequence for the binding of the RBF is suggested to be a palindromic octameric sequence TGACGTCA, which is identical to the consensus sequence of the cAMP-responsive element (CRE) of animal genes. Bacterially produced HBP-1b of wheat bound to the R-box, and its binding to mutated R-boxes was similar to that of RBF, suggesting that the RBF belongs to a family of bZIP-type plant nuclear factors that bind to CGTCA-related sequences. However, several differences between the RBF and HBP-1b were also noted.
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PMID:A nuclear factor that binds to a dyad-symmetric sequence with a CGTCA motif in the 5'-upstream region of the sweet potato beta-amylase gene. 802 23

Angiotensinogen is shown to be produced by the liver and the hepatoma cell line HepG2. As a first step for understanding the molecular relationship between the transcriptional regulation of the angiotensinogen gene and the pathogenesis of hypertension, we have analyzed the basal promoter of the angiotensinogen gene. Chloramphenicol acetyltransferase (CAT) assays with 5'-deleted constructs showed that the proximal promoter region from -96 to +22 of the transcriptional start site was enough to express HepG2-specific CAT activity. Electrophoretic mobility shift assay and DNase I footprinting demonstrated that the liver- and HepG2-specific nuclear factor (angiotensinogen gene-activating factor [AGF2]) and ubiquitous nuclear factor (AGF3) bound to the proximal promoter element from -96 to -52 (angiotensinogen gene-activating element [AGE2]) and to the core promoter element from -6 to +22 (AGE3), respectively. The site-directed disruption of either AGE2 or AGE3 decreased CAT expression, and the sequential titration of AGF3 binding by in vivo competition remarkably suppressed HepG2-specific CAT activity. Finally, the heterologous thymidine kinase promoter assay showed that AGE2 and AGE3 synergistically conferred HepG2-specific CAT expression. These results suggest that the synergistic interplay between AGF2 and AGF3 is important for the angiotensinogen promoter activation.
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PMID:Molecular mechanism of transcriptional activation of angiotensinogen gene by proximal promoter. 816 41

Protein-DNA interactions in the promoter regions of two maize histone genes have been analyzed by DNase I and DMS in vivo footprinting combined with LMPCR amplification. Both promoters present a bimodular structure characterized by a proximal cell division-specific set of interactions and a distal region which displays constitutive footprints but enhancement of these footprints upon cell proliferation. The inducible region contains two cis-elements common to all replication-dependent plant histone genes, one of them having previously been shown to be a target for the wheat nuclear protein HBP-2. In the constitutive region, the first demonstration for the existence of a transcription factor binding to the highly conserved plant histone-specific octamer CGCGGATC is provided. Exchange of cell-type-specific factors is postulated to occur at that site. Additional immediate upstream constitutive elements binding regulatory proteins include a degenerate octameric sequence, a CCAAT-box, a CACCC sequence and composite ACGTCA/ACGTGG hexameric sequences binding HBP-1-related trans-acting factors. The close proximity of these elements within the constitutive region and the redundancy of some of them suggest complex cooperation and competition mechanisms contributing to achieve the final expression level and likely also to mediate the interplay between constitutive and inducible factors.
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PMID:Constitutive and cell-division-inducible protein-DNA interactions in two maize histone gene promoters. 822 Apr 90

Atrial natriuretic peptide (ANP) is a potent diuretic, natriuretic, and vasorelaxant hormone that is expressed early in ventricular hypertrophy. Expression of human ANP is controlled by a series of regulatory elements located in the 5' flanking sequence of its gene. We generated a series of 5' deletion mutations extending from -2600 to -1150 relative to the transcription start site and linked them to a chloramphenicol acetyltransferase reporter gene. Using transient transfection analysis, we have identified a negative regulatory element between -1206 and -1152 relative to the start site. Each of a series of 5' deletion mutants, when introduced into fibroblast cultures, expressed the reporter function at a level that was significantly less (< 20%) than that seen with the -1152 reporter construct, whereas comparably transfected atrial cardiocytes demonstrated no change in reporter activity, implying that the repressor function is specific to cell type. The critical region (from -1206 to -1152) associates with a soluble protein present in cardiac fibroblast extracts in a sequence-specific fashion. Deoxyribonuclease I footprint analysis demonstrated the presence of several protected regions, including one that overlies an E-box motif (CAACTG), an element that in other systems has been implicated in promoting differentiation in the myocyte lineage. Site-directed mutagenesis of the E-box motif suppressed both the protein-binding and inhibitory activities of the 54-bp fragment. In summary, we have found a region in the 5' flanking sequence of the human ANP gene that represses transcriptional activity in nonmyocardial cells. This element may play an important role in the restriction of ANP gene expression to cardiac myocytes.
Hypertension 1996 Aug
PMID:An E-box motif conveys inhibitory activity on the atrial natriuretic peptide gene. 870

Pseudomonas azelaica HBP1 can use 2-hydroxybiphenyl (2-HBP) and 2,2'-dihydroxybiphenyl as sole carbon and energy sources by means of the hbp regulon. This regulon is composed of three genes, hbpCA and hbpD, coding for enzymes of a meta-cleavage pathway and the hbpR gene, which codes for a XylR/DmpR-type transcription regulator. It was previously shown that HbpR activates transcription from two sigma(54)-dependent promoters, P(hbpC) and P(hbpD), in the presence of 2-HBP. In this study, by using gel mobility shift assays with a purified fusion protein containing calmodulin binding protein (CBP) and HbpR, we detected two binding regions for HbpR in P(hbpC) and one binding region in P(hbpD). DNase I footprints of the proximal binding region of P(hbpC) and of the binding region in P(hbpD) showed that CBP-HbpR protected a region composed of two inverted repeat sequences which were homologous to the binding sites identified for XylR. Unlike the situation in the XylR/P(u) system, we observed simultaneous binding of CBP-HbpR on the two upstream activating sequences (UASs). Fragments with only one UAS did not show an interaction with HbpR, indicating that both pairs of UASs are needed for HbpR binding. The addition of both ATP and 2-HBP increased the DNA binding affinity of HbpR. These results showed for the first time that, for regulators of the XylR/DmpR type, the effector positively affects the recruitment of the regulatory protein on the enhancer DNA.
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PMID:Identification and physical characterization of the HbpR binding sites of the hbpC and hbpD promoters. 1200 31

Caspase-activated DNase (CAD) is a double-strand-specific endonuclease that is responsible for the cleavage of nucleosomal spacer regions and subsequent chromatin condensation during apoptosis. Given that several endonucleases (eg, DNase I, DNase II, and Endog) have been shown to regulate pathological cardiac hypertrophy, we questioned whether CAD, which is critical for the induction of DNA fragmentation, plays a pivotal role in pressure overload-elicited cardiac hypertrophy. A CAD-knockout mouse model was generated and subjected to aortic banding for 8 weeks. The extent of cardiac hypertrophy was evaluated by echocardiography and pathological and molecular analyses. Our results demonstrated that the disruption of CAD attenuated pressure overload-induced cardiac hypertrophy, fibrosis, and cardiac dysfunction. Conversely, transgenic mice with cardiac-specific overexpression of CAD showed an aggravated cardiac hypertrophic response to chronic pressure overload. Mechanistically, we discovered that the expression and activation of mitogen-activated protein kinase-extracellular signal-regulated kinase 1/2 was significantly reduced in the CAD-knockout hearts compared with the control hearts; however, they were greatly increased in the CAD-overexpressing hearts after aortic banding. Similar results were observed in ex vivo cultured neonatal rat cardiomyocytes after treatment with angiotensin II for 48 hours. These data indicate that CAD functions as a necessary modulator of the hypertrophic response by regulating the mitogen-activated protein kinase-extracellular signal-regulated kinase 1/2 signaling pathway in the heart. Our study suggests that CAD might be a novel target for the treatment of pathological cardiac hypertrophy and heart failure.
Hypertension 2015 Apr
PMID:Novel role for caspase-activated DNase in the regulation of pathological cardiac hypertrophy. 2564 92

Genome-wide association studies have proven the highly polygenic architecture of complex diseases or traits; therefore, single-locus-based methods are usually unable to detect all involved loci, especially when individual loci exert small effects. Moreover, the majority of associated single-nucleotide polymorphisms resides in non-coding regions, making it difficult to understand their phenotypic contribution. In this work, we studied epistatic interactions associated with three common diseases using Korea Association Resource (KARE) data: type 2 diabetes mellitus (DM), hypertension (HT), and coronary artery disease (CAD). We showed that epistatic single-nucleotide polymorphisms (SNPs) were enriched in enhancers, as well as in DNase I footprints (the Encyclopedia of DNA Elements [ENCODE] Project Consortium 2012), which suggested that the disruption of the regulatory regions where transcription factors bind may be involved in the disease mechanism. Accordingly, to identify the genes affected by the SNPs, we employed whole-genome multiple-cell-type enhancer data which discovered using DNase I profiles and Cap Analysis Gene Expression (CAGE). Assigned genes were significantly enriched in known disease associated gene sets, which were explored based on the literature, suggesting that this approach is useful for detecting relevant affected genes. In our knowledge-based epistatic network, the three diseases share many associated genes and are also closely related with each other through many epistatic interactions. These findings elucidate the genetic basis of the close relationship between DM, HT, and CAD.
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PMID:Understanding Epistatic Interactions between Genes Targeted by Non-coding Regulatory Elements in Complex Diseases. 2570 56

We recently demonstrated that selective expression of the Rho GTPase-activating protein ARHGAP42 in smooth muscle cells (SMCs) controls blood pressure by inhibiting RhoA-dependent contractility, providing a mechanism for the blood pressure-associated locus within the ARHGAP42 gene. The goals of the current study were to identify polymorphisms that affect ARHGAP42 expression and to better assess ARHGAP42's role in the development of hypertension. Using DNase I hypersensitivity methods and ENCODE data, we have identified a regulatory element encompassing the ARHGAP42 SNP rs604723 that exhibits strong SMC-selective, allele-specific activity. Importantly, CRISPR/Cas9-mediated deletion of this element in cultured human SMCs markedly reduced endogenous ARHGAP42 expression. DNA binding and transcription assays demonstrated that the minor T allele variation at rs604723 increased the activity of this fragment by promoting serum response transcription factor binding to a cryptic cis-element. ARHGAP42 expression was increased by cell stretch and sphingosine 1-phosphate in a RhoA-dependent manner, and deletion of ARHGAP42 enhanced the progression of hypertension in mice treated with DOCA-salt. Our analysis of a well-characterized cohort of untreated borderline hypertensive patients suggested that ARHGAP42 genotype has important implications in regard to hypertension risk. Taken together, our data add insight into the genetic mechanisms that control blood pressure and provide a potential target for individualized antihypertensive therapies.
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PMID:Blood pressure-associated polymorphism controls ARHGAP42 expression via serum response factor DNA binding. 2816 5


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