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)

A variety of systems use nucleoside triphosphate hydrolysis to control or provide energy for biological processes, mediated through protein-protein interactions. The nature of this coupling may vary, but often there is a degree of similarity. In this paper, two systems are compared: actomyosin in muscle and p21ras in a signal transduction pathway as yet undefined. The mechanism of the nucleotide triphosphate hydrolysis and the consequent changes in the protein-nucleotide complex have been investigated, to understand how the coupling to biological function is achieved. The basal nucleoside triphosphatase mechanisms are compared and the roles of proteins that activate the hydrolysis, actin and GAP, are discussed. The cleavage process was probed by stereochemical techniques to determine the basic mechanism, of either a phosphorylated enzyme intermediate or direct displacement of nucleoside diphosphate by water. Phosphate-water oxygen exchange probes were used to investigate nucleoside triphosphate and inorganic phosphate release steps. A new method of probing the kinetics of inorganic phosphate release directly has been developed. In muscle, this process seems likely to be related directly to force generation. In the GAP-ras system, measurement of phosphate release is allowing the mechanism of the GAP-p21ras interaction to be probed.
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PMID:The role of nucleoside triphosphate hydrolysis in transducing systems: p21ras and muscle. 135 Dec 91

Three normal human diploid cell strains were transfected with an activated Ha-ras oncogene (EJ ras) or SV40 T-antigen. Multiple clones were examined for morphological alterations, growth requirements, ability to grow under anchorage independent conditions, immortality and tumorigenicity in nude mice. Clones expressing SV40 T-antigen alone or in combination with ras protein p21 were significantly radioresistant as compared with their parent cells or clones transfected with the neo gene only. This radioresistant phenotype persisted in post-crisis, immortalized cell lines. Cells transfected with EJ ras alone showed no morphological alterations nor significant changes in radiosensitivity. Cell clones expressing ras and/or SV40 T-antigen showed a reduced requirement for serum supplements, an increase in aneuploidy and chromosomal aberrations, and enhanced growth in soft agar as an early cellular response to SV40 T-antigen expression. The sequential order of transfection with SV40 T-antigen and ras influenced radio-sensitivity but not the induction of morphological changes. These data suggest that expression of the SV40 T-antigen but not activated Ha-ras plays an important role in the radiosensitivity of human diploid cells. The radioresistant phenotype in SV40 T transfected cells was not related to the enhanced level of genetic instability seen in pre-crisis and newly immortalized cells, nor to the process of immortalization itself.
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PMID:Transformation and radiosensitivity of human diploid skin fibroblasts transfected with activated ras oncogene and SV40 T-antigen. 135 14

The interaction between the low molecular weight G protein ras p21 and a guanosine triphosphatase activating protein (GAP) uncouples a heterotrimeric G protein (Gk) from muscarinic receptors. Through the use of isolated atrial cell membranes and genetically engineered GAP deletion mutants, the src homology regions (SH2-SH3) at the amino terminus of GAP have been identified as the domains responsible for this effect. Deletion of the domain required to stimulate the guanosine triphosphatase activity of ras p21 relieves the requirement for ras p21 in this system. A model is presented that suggests that ras p21 induces a conformational change in GAP, which allows the SH2-SH3 regions of GAP to function.
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PMID:GAP domains responsible for ras p21-dependent inhibition of muscarinic atrial K+ channel currents. 155 41

The gene for von Recklinghausen neurofibromatosis (NF1) was recently identified by positional cloning and found to code for a large, ubiquitously expressed protein. This protein has both structural and functional similarity to a family of proteins with guanosine triphosphatase-activating properties, involved in the regulation of the protooncogene ras. One of the postulated functions of the NF1 gene product may relate to its ability to regulate ras-mediated cell proliferation. Selective pharmacotherapy directed at downregulating ras may be of benefit to patients with NF1.
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PMID:Recent progress toward understanding the molecular biology of von Recklinghausen neurofibromatosis. 159 91

Granulosa cell lines, transformed by SV40 T-antigen and Ha-ras oncogene, have recently been established that can produce progesterone at levels comparable to those of highly differentiated cultures of primary granulosa cells (1-4). Here, the hypothesis that these cells contain a mitochondrial benzodiazepine receptor, and that stimulation of the receptor can trigger progesterone production in these cells, was tested. The agonist of the peripheral benzodiazepine receptor, Ro5-4864, produced a 3- to 5-fold stimulation (P less than 0.005) of progesterone production both in differentiated granulosa primary cultures and in the oncogene-transformed cell lines. Ro5-2807 (diazepam, Valium) exerts a similar effect on granulosa cell steroidogenesis while the specific agonist of central benzodiazepine receptor Ro15-4513 was without effect. The effects of Ro5-4864 or Ro5-2807 were not additive to those of gonadotropins and cAMP. Intact isolated mitochondria possessed high-affinity binding sites to [3H]-Ro5-4864 (Kd = 3.03 +/- 0.70 nM), which were enriched by 1 order of magnitude in these organelles compared to total cell homogenate. Bound Ro5-4864 could be competitively displaced with 1 microM unlabeled Ro5-4864 and Ro5-2807, but not with specific ligands of central benzodiazepine receptors Ro15-4513 and Ro15-1788. Prolonged elevation of cAMP in these cells caused a 30% (P less than 0.01) rise in the number of receptors. Mitochondria of NIH 3T3 cells contained only 30-40% (P less than 0.001) of the Ro5-4864 binding sites of mitochondria from steroidogenic cells, whereas yeast mitochondria lacked them completely. The existence of functional peripheral benzodiazepine receptors in mitochondria suggests that they may have a physiological role in the mobilization of cholesterol into mitochondria, and in elevating progesterone production in ovarian cells. The modulation of the interaction between benzodiazepine compounds and the gamma-aminobutyric acid receptor by progesterone metabolites suggests new interrelationships between peripheral and central nervous system receptors sensitive to benzodiazepines.
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PMID:An inducible functional peripheral benzodiazepine receptor in mitochondria of steroidogenic granulosa cells. 164 7

The recA protein catalyses the ATP-driven homologous pairing and strand exchange of DNA molecules. It is an allosteric enzyme: the ATPase activity is DNA-dependent, and ATP-bound recA protein has a high affinity for DNA, whereas the ADP-bound form has a low affinity. In the absence of ATP hydrolysis, recA protein can still promote homologous pairing, apparently through the formation of a triple-stranded intermediate. The exact role of ATP hydrolysis is not clear, but it presumably drives the triplex intermediate towards products. Here we determine the position of bound ADP diffused into the recA crystal. We show that only the phosphates are bound in the same way as in other NTPases containing the G/AXXXXGKT/S motif. We propose that recA protein may change its conformation upon ATP hydrolysis in a manner analogous to one such protein, the p21 protein from the ras oncogene. A model is presented to account for the allosteric stimulation of DNA binding by ATP. The mechanism by which nucleoside triphosphate hydrolysis is coupled to the binding of another ligand in recA protein and p21 may be typical of the large class of NTPases containing this conserved motif.
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PMID:Structure of the recA protein-ADP complex. 173 Dec 43

Dichloroacetic acid (DCA) has recently been shown to increase significantly the incidence of hepatic adenomas (HAs) and hepatocarcinomas (HCs) in male B6C3F1 mice. Although little is known about the mechanism of DCA carcinogenesis, chronic ingestion of the compound in drinking water induces primarily hyperplastic nodules (HNs) prior to the appearance of HAs and HCs. Given the putative preneoplastic potential of the HNs, we undertook this study to determine the role of the HNs in the progression of DCA-induced hepatocarcinogenesis. This role was assessed by detecting the expression of five different tumor markers: p21 ras, p39 c-jun, phosphotyrosine, tumor-associated aldehyde dehydrogenase and alpha-fetoprotein, all known from previous studies to be expressed more often in neoplastic liver lesions than in normal liver. Tumor marker expression was detected by immunohistochemical methods using formalin-fixed, paraffin-embedded sections of normal B6C3F1 mouse liver, and DCA-induced HNs, HAs and HCs. The results demonstrated that, except for the c-jun marker, HNs expressed the markers significantly less often than either HAs or HCs. Equal expression of c-jun occurred in any of the three lesion types. Although these results could be used to argue that no relationship existed between HNs and later-appearing HAs and HCs, those HNs that were marker positive contained small nests of marker-positive hepatocytes among a field of normally appearing unstained hepatocytes. No similar nests of marker-positive cells were detected in any area of normal liver outside the HNs. Also very few altered hepatic foci (AF) were detected with these markers or with hematoxylin and eosin, or with histochemical stains for ATPase or glucose-6-phosphatase deficiencies. These results suggested that these nests within some HNs were areas of transformed, or neoplastic hepatocytes. Phenotypic heterogeneity analysis, in which the number of tumor markers co-expressed by any given lesion was examined, confirmed a significantly greater percentage of HAs and HCs expressing multiple markers than HNs. Those HNs that expressed multiple markers, however, expressed at the same frequency as HAs and HCs and the expression was confined to the same nests of cells. Taken together, these data suggest that these nests of marker-positive cells within the HNs were neoplastic and could develop into later-appearing HAs and/or HCs. The absence of marker expression in normal liver and limited expression in the few AF indicates that the HNs may be the only significant preneoplastic lesion in DCA-induced hepatocarcinogenesis.
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PMID:The role of hyperplastic nodules in dichloroacetic acid-induced hepatocarcinogenesis in B6C3F1 male mice. 186 Jan 58

The expression of Ha-ras in quiescent NIH3T3 cells carrying a glucocorticoid-inducible human Ha-ras gene (Val-Gly mutation at codon 12) stimulates total 86Rb+ influx. This effect is predominantly due to an elevated 86Rb+ uptake through an ouabain-resistant, furosemide-sensitive system. The ouabain-sensitive Na+/K(+)-ATPase is less affected. The transport which is resistant to both inhibitors is not altered by Ha-ras. Overexpression of the Ha-ras proto-oncogene causes only a marginal increase in total 86Rb+ uptake. The stimulation of the furosemide-sensitive influx by Ha-ras is paralleled by an increase in mean cell volume which can be inhibited by furosemide. A rapid stimulation of the furosemide-sensitive Rb+ influx is also observed after addition of bombesin to growth-arrested cells. Furosemide inhibits the mitogenic response after expression of Ha-ras or addition of bombesin. Both the Ha-ras and the bombesin-induced stimulation of the furosemide-sensitive Rb+ transport can be blocked by protein kinase C depletion or the protein kinase C inhibitor staurosporine. In contrast to bombesin-induced phosphatidylinositol-4,5-bisphosphate hydrolysis which is down-modulated by Ha-ras, the stimulation of the furosemide-sensitive Rb+ influx by bombesin is elevated in Ha-ras-expressing cells. This is in accordance with the increased mitogenic activity of bombesin in Ha-ras-expressing cells.
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PMID:Stimulation of K+ transport systems by Ha-ras. 202 40

To understand the molecular mechanism of endometrial differentiation we have initiated an analysis of the uteroglobin promoter. Uteroglobin is normally expressed in endometrial tissues under the control of ovarian hormones. In gene transfer experiments with the Ishikawa cell line, derived from a human endometrial adenocarcinoma, we have identified several regions in the promoter of the uteroglobin gene that are responsible for its endometrium-specific expression. To evaluate the generality of these findings, we have begun cloning the promoter regions of potential endometrial markers, including the rat, mouse, and human uteroglobin gene. In the rat, expression of the uteroglobin-like gene, CC10, is dominant in the lung but is also observed in the endometrium of progesterone treated animals. A comparison of the 5'-flanking sequence of the rat and rabbit uteroglobin gene resulted in the detection of similarities and differences that could explain their differential expression in vivo. To substantiate these findings we have established several cell lines from rat endometrium using murine retroviral vectors containing a positive selection marker and various viral oncogenes, such as SV40 large T antigen, adenovirus E1A, and Ha-ras. Cell lines immortalized by SV40 T-antigen were subsequently transformed with the Ha-ras oncogene. Several cell lines exhibit properties of epithelial endometrial cells. Two cell lines generated with a temperature sensitive mutant of the SV40 large T-antigen grow as transformed cells at the permissive temperature, but differentiate upon shifting to the non-permissive temperature. These rat endometrial cell lines should be useful for the analysis of endometrium-specific gene expression and as model systems for endometrial carcinoma.
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PMID:Expression of the uteroglobin promoter in epithelial cell lines from endometrium. 206 10

A short sequence motif rich in glycine residues, Gly-X-X-X-X-Gly-Lys-Thr/Ser, has been found in many nucleotide-binding proteins including the beta subunit of Escherichia coli H(+)-ATPase (Gly-Gly-Ala-Gly-Val-Gly-Lys-Thr, residues 149-156). The following mutations were introduced in this region of the cloned E. coli unc operon carried by a plasmid pBWU1: Ala-151----Pro or Val; insertion of a Gly residue between Lys-155 and Thr-156; and replacement of the region by the corresponding sequence of adenylate kinase (Gly-Gly-Pro-Gly-Ser-Gly-Lys-Gly-Thr) or p21 ras protein (ras) (Gly-Ala-Gly-Gly-Val-Gly-Lys-Ser). All F0F1 subunits were synthesized in the deletion strain of the unc operon-dependent on pBWU1 with mutations, and essentially the same amounts of H(+)-ATPase with these mutant beta subunits were found in membranes. The adenylate kinase and Gly insertion mutants showed no oxidative phosphorylation or ATPase activity, whereas the Pro-151 mutants had higher ATPase activity than the wild-type, and the Val-151 and ras mutants had significant activity. It is striking that the enzyme with the ras mutation (differing in three amino acids from the beta sequence) had about half the membrane ATPase activity of the wild-type. These results together with the simulated three-dimensional structures of the wild-type and mutant sequences suggest that in mutant beta subunits with no ATPase activity projection of Thr-156 residues was opposite to that in the wild-type, and that the size and direction of projection of residue 151 are important for the enzyme activity.
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PMID:The glycine-rich sequence of the beta subunit of Escherichia coli H(+)-ATPase is important for activity. 214 31


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