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)

One of the profound changes in cellular morphology which occurs during mitosis is a massive alteration in the organization of the microfilament cytoskeleton. This change, together with other mitotic events including nuclear membrane breakdown, chromosome condensation and formation of mitotic spindles, is induced by a molecular complex called maturation promoting factor. This consists of at least two subunits, a polypeptide of relative molecular mass 45,000-62,000 (Mr 45-62K) known as cyclin, and a 34K catalytic subunit which has serine/threonine kinase activity and is known as cdc2 kinase. Non-muscle caldesmon, an 83K actin- and calmodulin-binding protein, is dissociated from microfilaments during mitosis, apparently as a consequence of mitosis-specific phosphorylation. We now report that cdc2 kinase phosphorylates caldesmon in vitro principally at the same sites as those phosphorylated in vivo during mitosis, and that phosphorylation reduces the binding affinity of caldesmon for both actin and calmodulin. Because caldesmon inhibits actomyosin ATPase, our results suggest that cdc2 kinase directly causes microfilament reorganization during mitosis.
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PMID:Phosphorylation of non-muscle caldesmon by p34cdc2 kinase during mitosis. 198 9

Rb represses E2F-mediated transcription in part by blocking the trans-activation domain of E2F. In addition, Rb can convert an E2F binding site from a positive to a negative element. To examine the effect of a Rb-DNA-bound complex on transcription, full-length Rb was fused to the DNA binding domain of GAL4. Here, we report that GAL4-Rb can repress transcription mediated by either Sp1, AP-1, or p53, dependent upon the presence of both the GAL4 DNA binding domain and GAL4 binding sites. Moreover, GAL4-Rb inhibited the activity of the herpes simplex virus tk promoter from GAL4 binding sites located at a distance from the promoter. In contrast, GAL4-Rb was unable to repress basal transcription. Cotransfection of specific cyclins and cyclin-dependent kinases or SV40 T-antigen abolished the repressive activity of GAL4-Rb. The domains of Rb involved in mediating the repression of transcription were mapped to regions that are overlapping, but not identical, to those required for the interaction with E2F. We propose that Rb can function as a general repressor of transcription when bound to the promoter region.
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PMID:The retinoblastoma susceptibility gene product represses transcription when directly bound to the promoter. 772 91

We have compared the periodic fluctuation of mRNAs encoded by CDC6, a cell cycle gene controlling initiation of DNA replication, and CLN1, a G1 cyclin gene expressed at late G1. The maxima of CDC6 mRNA precede those of CLN1 mRNA by about 15 min in cells synchronized by release from pheromone arrest or from a cdc15 thermal arrest. CDC6 mRNA accumulates in cdc15-arrested telophase cells, decays around cell separation, and reappears during telophase and nuclear division of the next cycle. CDC6 transcription at late mitosis is not affected by the pheromone signaling pathway. The CDC6 mRNA fluctuation pattern is imposed to a CLN1-derived reporter gene if fused to the CDC6 promoter. The CDC6 gene was expressed in Escherichia coli as a glutathione-S-transferase fusion protein and purified by affinity chromatography. The Cdc6 protein binds rATP and rGTP upon UV cross-linking and catalyzes the DNA-independent hydrolysis of purine nucleoside triphosphates, but does not appear to interact directly with DNA. The Cdc6 protein may control the ATP-dependent initiation of replication by conferring ATPase activity to an origin-recognizing complex.
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PMID:The Saccharomyces cerevisiae CDC6 gene is transcribed at late mitosis and encodes a ATP/GTPase controlling S phase initiation. 808 40

In human fibroblasts, growth arrest at the end of the normal proliferative life span (induction of senescence) is dependent on the activity of the tumor suppressor protein p53. In contrast, once senescence has been established, it is generally accepted that reinitiation of DNA synthesis requires loss of multiple suppressor pathways, for example, by expression of Simian virus 40 (SV40) large T antigen, and that even this will not induce complete cell cycle traverse. Here we have used microinjection of monoclonal antibodies to the N terminus of p53, PAb1801 and DO-1, to reinvestigate the effect of blocking p53 function in senescent human fibroblasts. Unexpectedly, we found that both antibodies induce senescent cells to reenter S phase almost as efficiently as SV40, accompanied by a reversion to the "young" morphology. Furthermore, this is followed by completion of the cell division cycle, as shown by the appearance of mitoses, and by a four- to fivefold increase in cell number 9 days after injection. Immunofluorescence analysis showed that expression of the p53-inducible cyclin/kinase inhibitor p21sdi1/WAF1 was greatly diminished by targeting p53 with either PAb1801 or DO-1 but remained high and, moreover, still p53 dependent in cells expressing SV40 T antigen. As previously observed for induction, the maintenance of fibroblast senescence therefore appears to be critically dependent on functional p53. We suggest that the previous failure to observe this by using SV40 T-antigen mutants to target p53 was most probably due to incomplete abrogation of p53 function.
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PMID:Reinitiation of DNA synthesis and cell division in senescent human fibroblasts by microinjection of anti-p53 antibodies. 948 78

We investigated the ability of endocytosed activated epidermal growth factor receptors (EGFR) to induce expression of the cyclin-interacting protein p21/CIP1 in A431 cells. Transforming growth factor alpha (TGFalpha) and EGF both induced tyrosine phosphorylation, induction of p21/CIP1, and thereby inhibition of DNA synthesis. TGFalpha is released from the EGFR when the TGFalpha-EGFR complex encounters low pH upon endocytosis. Consistently, we found more rapid dephosphorylation of the EGFR and less induction of p21/CIP1 by TGFalpha than by EGF. This difference was abolished upon neutralizing endosomal pH by the carboxylic ionophore monensin or the proton ATPase inhibitor bafilomycin A1. When surface-bound TGFalpha was removed by acid stripping and endosomal pH was neutralized with bafilomycin A1, TGFalpha stimulated EGFR tyrosine phosphorylation, induced p21/CIP1, and inhibited DNA synthesis. This strongly suggests that p21/CIP1 can be induced by endocytosed, activated EGFR and that endocytosed EGFR can affect cell growth.
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PMID:Endocytosed epidermal growth factor (EGF) receptors contribute to the EGF-mediated growth arrest in A431 cells by inducing a sustained increase in p21/CIP1. 971 60

In the yeast Saccharomyces cerevisiae, transcription of a secreted acid phosphatase, PHO5, is repressed in response to high concentrations of extracellular inorganic phosphate. To investigate the signal transduction pathway leading to transcriptional regulation of PHO5, we carried out a genetic selection for mutants that express PHO5 constitutively. We then screened for mutants whose phenotypes are also dependent on the function of PHO81, which encodes an inhibitor of the Pho80p-Pho85p cyclin/cyclin-dependent kinase complex. These mutations are therefore likely to impair upstream functions in the signaling pathway, and they define five complementation groups. Mutations were found in a gene encoding a plasma membrane ATPase (PMA1), in genes required for the in vivo function of the phosphate transport system (PHO84 and PHO86), in a gene involved in the fatty acid synthesis pathway (ACC1), and in a novel, nonessential gene (PHO23). These mutants can be classified into two groups: pho84, pho86, and pma1 are defective in high-affinity phosphate uptake, whereas acc1 and pho23 are not, indicating that the two groups of mutations cause constitutive expression of PHO5 by distinct mechanisms. Our observations suggest that these gene products affect different aspects of the signal transduction pathway for PHO5 repression.
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PMID:A genetic study of signaling processes for repression of PHO5 transcription in Saccharomyces cerevisiae. 983 15

We have previously reported on the development of an in vitro model system for studying the effect of hypoxia on ovarian carcinoma cell proliferation and invasion (Krtolica and Ludlow, 1996). These data indicate that the cell division cycle is reversibly arrested during the G1 phase. Here, we have continued this study to include the proliferation properties of both aerobic and hypoxic human ovarian carcinoma cells at the molecular level. The growth suppressor product of the retinoblastoma susceptibility gene, pRB, appears to be functional in these cells as determined by SV40 T-antigen binding studies. Additional G1-to-S cell cycle regulatory proteins, cyclins D and E, cyclin-dependent kinases (cdks) 4 and 2, and cdk inhibitors p27 and p18, also appear to be intact based on their apparent molecular weights and cell cycle stage-specific abundance. During hypoxia, there is a decrease in abundance of cyclins D and E, with an increase in p27 abundance. cdk4 activity towards pRB and cdk2 activity towards histone H1 are also decreased. Co-precipitation studies revealed an increased amount of p27 complexing with cyclin E-cdk2 during hypoxia than during aerobic cell growth. In addition, pRB-directed phosphatase activity was found to be greater in hypoxic than aerobic cells. Taken together, a model is suggested to explain hypoxia-induced cell cycle arrest in SKA human ovarian carcinoma cells.
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PMID:Molecular analysis of selected cell cycle regulatory proteins during aerobic and hypoxic maintenance of human ovarian carcinoma cells. 1047 Oct 34

By selectively eliminating ubiquitin-conjugated proteins, the 26S proteasome plays a pivotal role in a large variety of cellular regulatory processes, particularly in the control of cell cycle transitions. Access of ubiquitinated substrates to the inner catalytic chamber within the 20S core particle is mediated by the 19S regulatory particle (RP), whose subunit composition in budding yeast has been recently elucidated. In this study, we have investigated the cell cycle defects resulting from conditional inactivation of one of these RP components, the essential non-ATPase Rpn3/Sun2 subunit. Using temperature-sensitive mutant alleles, we show that rpn3 mutations do not prevent the G(1)/S transition but cause a metaphase arrest, indicating that the essential Rpn3 function is limiting for mitosis. rpn3 mutants appear severely compromised in the ubiquitin-dependent proteolysis of several physiologically important proteasome substrates. Thus, RPN3 function is required for the degradation of the G(1)-phase cyclin Cln2 targeted by SCF; the S-phase cyclin Clb5, whose ubiquitination is likely to involve a combination of E3 (ubiquitin protein ligase) enzymes; and anaphase-promoting complex targets, such as the B-type cyclin Clb2 and the anaphase inhibitor Pds1. Our results indicate that the Pds1 degradation defect of the rpn3 mutants most likely accounts for the metaphase arrest phenotype observed. Surprisingly, but consistent with the lack of a G(1) arrest phenotype in thermosensitive rpn3 strains, the Cdk inhibitor Sic1 exhibits a short half-life regardless of the RPN3 genotype. In striking contrast, Sic1 turnover is severely impaired by a temperature-sensitive mutation in RPN12/NIN1, encoding another essential RP subunit. While other interpretations are possible, these data strongly argue for the requirement of distinct RP subunits for efficient proteolysis of specific cell cycle regulators. The potential implications of these data are discussed in the context of possible Rpn3 function in multiubiquitin-protein conjugate recognition by the 19S proteasomal regulatory particle.
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PMID:Functional characterization of rpn3 uncovers a distinct 19S proteasomal subunit requirement for ubiquitin-dependent proteolysis of cell cycle regulatory proteins in budding yeast. 1049 Jun 25

As part of an ongoing project to understand the molecular mechanisms of fruit body development in Lentinula edodes (Shiitake mushroom), RNA fingerprinting by arbitrarily primed PCR (RAP-PCR) was used to identify differentially expressed genes in RNA populations from four stages of L. edodes development vegetative mycelium, primordium, young fruit body and mature fruit body. From 30 RNA fingerprints, we cloned and sequenced 33 RAP fragments after their differential expression patterns had been verified by reverse Northern dot-blot hybridization. Thirteen RAP fragments show high sequence similarity to known gene products which are involved in (1) transport across the plasma membrane (drug efflux pump and sugar transporter); (2) cell cycle control (cyclin B); (3) signal transduction and transcriptional regulation (mitogen-activated protein kinase, Cdc39/Not1, PriA, Jun-D); (4) intracellular molecule trafficking (ubiquitin, plasma membrane proton ATPase, and alpha-adaptin); (5) mitochondrial biogenesis (mitochondrial processing peptidase beta-subunit, mitochondrial glycerol-3-phosphate dehydrogenase); and (6) intermediary metabolism (fructose 1,6 bisphosphatase). The transcript levels for plasma membrane proton ATPase and alpha-adaptin remained constant, whereas the other eleven genes were differentially expressed during L. edodes. development. The expression profiles of the genes suggest that transport across the plasma membrane is important in the mycelial stage. Specific signal transduction and transcriptional controls may play important roles during the initiation of primordia and the formation of young fruiting bodies. When the mushroom matures, expression of genes involved in metabolic pathways becomes prominent. The isolation of these genes indicates their involvement in homobasidiomycete development and suggests new directions for molecular studies on mechanisms of mushroom development.
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PMID:Identification by RNA fingerprinting of genes differentially expressed during the development of the basidiomycete Lentinula edodes. 1066 59

Fertilization-induced Ca(2+) oscillations in mouse eggs cease at the time of pronuclear formation when maturation-promoting factor (MPF) is inactivated, but the Ca(2+) oscillations are ceaseless if eggs are arrested at metaphase by colcemid, which maintains the activity of MPF. To determine the possible role of MPF in regulation of cytoplasmic Ca(2+) excitability, roscovitine, a specific inhibitor of p34(cdc2)/cyclin B kinase, was used to inactivate MPF, and its effect on fertilization-induced Ca(2+) oscillations was investigated. Our results showed that roscovitine at >/= 50 microM suppressed fertilization-induced Ca(2+) oscillations in normal and colcemid-treated metaphase II (MII) eggs after the first 1-2 Ca(2+) spikes. Roscovitine inhibition of fertilization-induced Ca(2+) oscillations could be reversed by extensive washing of the eggs. Histone H1 kinase activity in colcemid-treated MII eggs was similarly inhibited by roscovitine, which suggested that the cessation of fertilization-induced Ca(2+) oscillations is due to the inactivation of MPF. Thimerosal-induced Ca(2+) oscillations in Ca(2+)-, Mg(2+)-free medium was also suppressed by roscovitine, suggesting a general inhibitory effect of roscovitine on Ca(2+) oscillations. The inhibition may be achieved by disruption of Ca(2+) release and refilling of the calcium store. Thapsigargin, an inhibitor of the endoplasmic reticulum Ca-ATPase, induced significantly less Ca(2+) release in roscovitine-treated eggs than in the non-drug-treated eggs. Taken together, our results suggest that MPF plays an important role in regulation of the cytoplasmic Ca(2+) excitability in mouse eggs.
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PMID:A specific inhibitor of p34(cdc2)/cyclin B suppresses fertilization-induced calcium oscillations in mouse eggs. 1072 55


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