Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) belong to the steroid/thyroid hormone superfamily of ligand-induced transcription factors. Both activate the human Na/K ATPase alpha1 and beta1 genes transcriptionally. To assess the role of the transcription factor Sp1 and the nuclear factor I (NF-I), in MR- and GR-mediated gene expression using the human Na/K ATPase beta1 full-length promoter, we have examined the functions of Sp-I and NF-I functions in two different cell lines, COS-1 and T-84. By transient transfections we have shown that Sp-I significantly enhances MR and GR expression, whereas NF-I had negligible effect. We propose that the transcriptional enhancement could be through a direct interaction physically between MR or GR with Sp1 that allows other factors to bind the responsive element resulting in synergistic upregulation of transcription.
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PMID:Upregulation of mineralocorticoid- and glucocorticoid-receptor gene expression by Sp-I. 1032 76

The transition of nonfailing to failing cardiac hypertrophy cannot be prevented by current drug regimens. This investigation examined whether possible drug targets have remained unexplored because they do not result in acute improvement of heart function. Of major importance, in this respect, is an inadequate performance of the sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA2). In the present approach, binding sequences within the proximal promoter of SERCA2 are described which may be useful in the development of drugs (i.e., transcriptional modulators) that interfere selectively with the transcription of genes of the cardiomyocyte. The proximal promoter region of the SERCA2 genes has a thyroid response element, 9 potential Sp1-binding sites (5'-GGGCGG-3', 5'-CCGCCC-3' and 5'-GGGAGG-3'), and an E-box motif (5'-CACATG-3'), which may function as glucose response elements. This region also has 2 putative fatty-acid response elements (5'-GGGGGA-3'). It is proposed that the beneficial effects of the camitine palmitoyltransferase-1 inhibitor etomoxir arise from a shift in fuel metabolism involving glucose response elements and/or peroxisomal proliferator-activated receptors. Although the relative contribution of these DNA regulatory elements remains to be defined, it appears that they provide the driving force that prevents the decrease in transcriptional activity of the SERCA2 gene in the hypertrophic heart. It is further concluded that etomoxir represents a member of a novel class of transcriptional modulators that improve function of hypertrophied hearts with unimpeded blood flow by modulating gene expression of the cardiomyocyte.
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PMID:Transcriptional modulators targeted at fuel metabolism of hypertrophied heart. 1075 May 84

Expression of Na,K-ATPase activity is up-regulated in cells incubated for extended intervals in the presence of low external K(+). Our previous data showed that exposure of cardiac myocytes to low K(+) increased the steady-state abundance of Na,K-ATPase beta1 subunit mRNA. In the present study we determined that incubation of primary cultures of neonatal rat cardiac myocytes with low K(+) augmented Na,K-ATPase beta1 gene expression at a transcriptional level and that this effect required extracellular Ca(2+). The stimulatory effect of low K(+) on Na,K-ATPase beta1 gene transcription was not dependent on increased contractile activity of cardiac myocytes. Na,K-ATPase beta1 5'-flanking region deletion plasmids used in transient transfection analysis demonstrated that the region between nucleotides -62 to -42 of the beta1 promoter contained a low K(+) response element. Site-directed mutagenesis of a potential GC box core motif GCG in the -58/-56 region of the beta1 promoter decreased basal and low K(+)-mediated transcription. Mutation of the core sequence of a putative GC box element located between nucleotides -101 and -99 further decreased the low K(+) effect on beta1 gene transcription. Electrophoretic mobility shift assays using oligonucleotides spanning the proximal and distal GC box elements of the beta1 promoter showed enhanced binding of two complexes in response to low K(+). The inclusion of a consensus GC box sequence as a competitor in gel shift analysis reduced factor binding to the low K(+) response elements. Antibodies to transcription factors Sp1 and Sp3 interacted with components of both DNA-binding complexes and binding of nuclear factors was abolished in gel shift studies using GC box mutants. Together these data indicate that enhanced binding of Sp1 and Sp3 to two GC box elements in the rat Na,K-ATPase beta1 subunit gene promoter mediates beta1 gene transcription up-regulation in neonatal rat cardiac myocytes exposed to low external K(+).
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PMID:Regulation of Na,K-ATPase beta 1 subunit gene transcription by low external potassium in cardiac myocytes. Role of Sp1 AND Sp3. 1081 58

The transcription factor Sp1 was previously shown to undergo proteasome-dependent degradation when cells were glucose-starved and stimulated with the adenylate cyclase inducer, forskolin. However, the control of the Sp1 degradation process is largely unknown. Using in vitro and in vivo interaction studies, we show in the present study that Sp1 interacts with human Sug1 [hSug1, also known as p45 or thyroid-hormone-receptor interacting protein ('TRIP1')], an ATPase subunit of the 26 S proteasome and a putative transcriptional modulator. This interaction with Sp1 occurs through the C-terminus of hSug1, the region that contains the conserved ATPase domain in this protein. Both in vitro studies, in reconstituted degradation assays, and in vivo experiments, in which hSug1 is overexpressed in normal rat kidney cells, show that full-length hSug1 is able to stimulate the proteasome-dependent degradation of Sp1. However, hSug1 truncations that lack either the N- or C-terminal domain of hSug1 act as dominant negatives, inhibiting Sp1 degradation in vitro. Also, an ATPase mutant of hSug1, while still able to bind Sp1, acts as a dominant negative, blocking Sp1 degradation both in vitro and in vivo. These results demonstrate that hSug1 is involved in the degradation of Sp1 and that ATP hydrolysis by hSug1 is necessary for this process. Our findings indicate that hSug1 is an exchangeable proteasomal component that plays a critical regulatory role in the proteasome-dependent degradation of Sp1. However, hSug1 is not the factor limiting Sp1 degradation in the cells treated with glucosamine. This and other considerations suggest that hSug1 co-operation with other molecules is necessary to target Sp1 for proteasome degradation.
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PMID:Human Sug1/p45 is involved in the proteasome-dependent degradation of Sp1. 1081 20

Androgen receptor (AR) belongs to the superfamily of nuclear hormone receptors that employ complex molecular mechanisms to guide the development and physiological functions of their target tissues. Our recent work has led to the identification of four novel proteins that recognize AR zinc-finger region (ZFR) both in vivo and in vitro. One is a small nuclear RING-finger protein that possesses separate interaction interfaces for AR and for other transcription activators such as Sp1. The second is a nuclear serine/threonine protein kinase (androgen-receptor-interacting nuclear protein kinase; ANPK); however, the receptor itself does not seem to be a substrate for this kinase. The third one is dubbed androgen-receptor-interacting protein 3 (ARIP3) and is a novel member of the PIAS (protein inhibitor of activated STAT) protein family. The fourth protein, termed ARIP4, is a nuclear ATPase that belongs to the SNF2-like family of chromatin remodelling proteins. All four proteins exhibit a punctate nuclear pattern when expressed in cultured cells. Each protein modulates AR-dependent transactivation in co-transfection experiments; their activating functions are not restricted to AR. Current work is aimed at elucidating the biochemical and functional properties of these AR-interacting proteins and at finding the partner proteins that form complexes with them in vivo.
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PMID:Androgen-receptor-interacting nuclear proteins. 1096 28

Although the gamma subunit of the Na,K-ATPase has only 66 or 68 amino acids, its human gene (FXYD2) was found to span 9.2 kb and have seven exons, including two alternatively spliced exons encoding different N-termini. Two candidate promoters with consensus sites for transcription factors Sp1, AP-1, and AP-2 are present, consistent with independent transcription of the splice variants. Multiple ESTs support the transcriptional competence of the identified gene elements. In the FXYD2 gene, there are two closely spaced polyadenylation signals, and both are used. A proposed third splice variant encoding a 31-residue N-terminal extension was not found in the gene, nor was the predicted larger protein found in human kidney Na,K-ATPase. Instead, evidence was found for the origin of the larger cDNA clone in homologous recombination with unrelated DNA from chromosome 2. FXYD2 is on chromosome 11q23 close to a site of tumorigenic chromosomal translocations, and has a number of repeat elements.
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PMID:Genomic organization of the human FXYD2 gene encoding the gamma subunit of the Na,K-ATPase. 1111 38

The vacuolar H+-ATPase (V-ATPase) is a multisubunit enzyme that couples ATP hydrolysis to proton pumping across membranes. The intracellular targeting and activity of the V-ATPase may be regulated via proteins that interact with the pump such as the accessory subunit Ac45. Here we report the isolation and characterization of the gene encoding Ac45. This single-copy gene is located in a gene-dense region of chromosome Xq and consists of 10 exons spanning approximately 8 kb in the mouse and human genomes. The gene structure is poorly conserved in that its invertebrate orthologs of Caenorhabditis elegans and Drosophila melanogaster encompass only six and four exons extending over 4.1 and 2.1 kb, respectively. Furthermore, the overall degree of amino acid sequence identity between the mammalian and invertebrate Ac45 proteins is very low (<18%), except for a surprisingly highly conserved putative targeting motif in the carboxy-terminal region. Primer extension analysis revealed that the mouse Ac45 gene contains two major transcription initiation sites. The start sites are not preceded by a clear CAAT-box and are located in a CpG island. The most downstream start site contains a TATA-box and transcriptional regulatory elements such as PEA-3, F2F, Maz and Sp1. The limited number of regulatory DNA elements common in the genes encoding Ac45 and V-ATPase subunits suggests a differential regulation of these genes. Together with the finding that Ac45 appears to occur only in multicellular organisms, these results indicate that this accessory subunit directs the V-ATPase to specialized and complex vacuolar systems.
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PMID:Structural gene organization and evolutionary aspects of the V-ATPase accessory subunit Ac45. 1199 89

We reported previously that the sarco(endo)plasmic reticulum Ca(2+)-ATPase type 3 (SERCA3) gene is expressed in many tissues and in a subset of cells such as endothelial, epithelial, and lymphoid lineages. Here we analyzed the mechanisms involved in the regulation of transcription of the SERCA3 gene in endothelial cells. The promoter of the murine SERCA3 gene was isolated, and a single transcription initiation site located 301 bp upstream of the translation initiation site was identified. Analysis of the transcriptional activity of fragments of the SERCA3 promoter showed the existence of a minimal promoter region located between bases -97 and +153 that contains one ETS-binding site (EBS) and two Sp1 elements that are essential for basal transcription. Mutation of the EBS or of the Sp1 sites abolished the basal activity of the promoter. We identified Ets-1 and Sp1 among endothelial nuclear factors that recognize the EBS and Sp1 sites on the promoter. Furthermore, transactivation of the -97/+301 promoter fragment by Ets-1 requires the presence of both the EBS and Sp1 sites, suggesting an interaction of the transcription factors on the gene promoter. Finally, overexpression of Ets-1 induced the expression of SERCA3 in endothelial cells and in fibroblasts.
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PMID:Basal transcription of the mouse sarco(endo)plasmic reticulum Ca2+-ATPase type 3 gene in endothelial cells is controlled by Ets-1 and Sp1. 1211 94

We have isolated two overlapping genomic clones that contain the 5'-terminal portion of the human vacuolar H(+)-ATPase c subunit (ATP6L) gene. The sequence preceding the transcription initiation site, which is GC-rich, contains four GC boxes and one Oct1-binding site, but there is no TATA box or CCAAT box. In vivo footprint analysis in human cancer cells shows that two GC boxes and the Oct1-binding site are occupied by Sp1 and Oct1, respectively. We show here that treatment with anticancer agents enhances ATP6L expression. Although cisplatin did not induce ATP6L promoter activity, it altered ATP6L mRNA stability. On the other hand, the DNA topoisomerase II inhibitor, TAS-103, strongly induced promoter activity, and this effect was completely eradicated when a mutation was introduced into the Oct1-binding site. Treatment with TAS-103 increased the levels of both Sp1/Sp3 and Oct1 in nuclear extracts. Cooperative binding of Sp1 and Oct1 to the promoter is required for promoter activation by TAS-103. Incubation of a labeled oligonucleotide probe encompassing the -73/-68 GC box and -64/-57 Oct1-binding site with a nuclear extract from drug-treated KB cells yielded higher levels of the specific DNA-protein complex than an extract of untreated cells. Thus, the two transcription factors, Sp1 and Oct1 interact, in an adaptive response to DNA damage, by up-regulating expression of the vacuolar H(+)-ATPase genes. Furthermore, combination of the vacuolar H(+)-ATPase (V-ATPase) inhibitor, bafilomycin A1, with TAS-103 enhanced apoptosis of KB cells with an associated increase in caspase-3 activity. Our data suggest that the induction of V-ATPase expression is an anti-apoptotic defense, and V-ATPase inhibitors in combination with low-dose anticancer agents may provide a new therapeutic approach.
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PMID:Enhanced expression of the human vacuolar H+-ATPase c subunit gene (ATP6L) in response to anticancer agents. 1213 27

UFD2a is a mammalian homolog of Saccharomyces cerevisiae Ufd2, originally described as an E4 ubiquitination factor. UFD2a belongs to the U-box family of ubiquitin ligases (E3s) and likely functions as both an E3 and E4. We have isolated and characterized the mouse gene (Ube4b) for UFD2a. A full-length (approximately 5700 bp) Ube4b cDNA was isolated and the corresponding gene spans >100 kb, comprising 27 exons. Luciferase reporter gene analysis of the 5(') flanking region of Ube4b revealed that nucleotides -1018 to -943 (relative to the translation initiation site) possess promoter activity. This functional sequence contains two putative Sp1 binding sites but not a TATA box. Immunoblot and immunohistochemical analyses revealed that UFD2a is expressed predominantly in the neuronal tissues. We also show that UFD2a interacts with VCP (a AAA-family ATPase) that is thought to mediate protein folding. These data implicate UFD2a in the degradation of neuronal proteins by the ubiquitin-proteasome pathway.
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PMID:Characterization of the mouse gene for the U-box-type ubiquitin ligase UFD2a. 1250 83


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