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

---

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

Proteasomes can exist in several different molecular forms in mammalian cells. The core 20S proteasome, containing the proteolytic sites, binds regulatory complexes at the ends of its cylindrical structure. Together with two 19S ATPase regulatory complexes it forms the 26S proteasome, which is involved in ubiquitin-dependent proteolysis. The 20S proteasome can also bind 11S regulatory complexes (REG, PA28) which play a role in antigen processing, as do the three variable gamma-interferon-inducible catalytic beta-subunits (e.g. LMP7). In the present study, we have investigated the subcellular distribution of the different forms of proteasomes using subunit specific antibodies. Both 20S proteasomes and their 19S regulatory complexes are found in nuclear, cytosolic and microsomal preparations isolated from rat liver. LMP7 was enriched approximately two-fold compared with core alpha-type proteasome subunits in the microsomal preparations. 20S proteasomes were more abundant than 26S proteasomes, both in liver and cultured cell lines. Interestingly, some significant differences were observed in the distribution of different subunits of the 19S regulatory complexes. S12, and to a lesser extent p45, were found to be relatively enriched in nuclear fractions from rat liver, and immunofluorescent labelling of cultured cells with anti-p45 antibodies showed stronger labelling in the nucleus than in the cytoplasm. The REG was found to be localized predominantly in the cytoplasm. Three- to six-fold increases in the level of REG were observed following gamma-interferon treatment of cultured cells but gamma-interferon had no obvious effect on its subcellular distribution. These results demonstrate that different regulatory complexes and subpopulations of proteasomes have different distributions within mammalian cells and, therefore, that the distribution is more complex than has been reported for yeast proteasomes.
...
PMID:Subcellular localization of proteasomes and their regulatory complexes in mammalian cells. 1065 52

In mammalian cells proteasomes can be activated by two different types of regulatory complexes which bind to the ends of the proteasome cylinder. Addition of two 19 S (PA700; ATPase) complexes forms the 26 S proteasome, which is responsible for ATP-dependent non-lysosomal degradation of intracellular proteins, whereas 11 S complexes (PA28; REG) have been implicated in antigen processing. The PA28 complex is upregulated in response to gamma-interferon (gamma-IFN) as are three non-essential subunits of the 20 S proteasome. In the present study we have investigated the effects of gamma-IFN on the level of different proteasome complexes and on the phosphorylation of proteasome subunits. After treatment of cells with gamma-IFN, the level of 26 S proteasomes decreased and there was a concomitant increase in PA28-proteasome complexes. However, no free 19 S regulatory complexes were detected. The majority of the gamma-IFN-inducible proteasome subunits LMP2 and LMP7 were present in PA28-proteasome complexes, but these subunits were also found in 26 S proteasomes. The level of phosphorylation of both 20 S and 26 S proteasome subunits was found to decrease after gamma-IFN treatment of cells. The C8 alpha subunit showed more than a 50% decrease in phosphorylation, and the phosphorylation of C9 was only barely detectable after gamma-IFN treatment. These results suggest that association of regulatory components to 20 S proteasomes is regulated, and that phosphorylation of proteasome alpha subunits may be one mode of regulation.
...
PMID:gamma-Interferon decreases the level of 26 S proteasomes and changes the pattern of phosphorylation. 1113 93

Proteasomes play a major role in non-lysosomal proteolysis and also in the processing of proteins for presentation by the MHC class I pathway. In animal cells they exist in several distinct molecular forms which contribute to the different functions. 26S proteasomes contain the core 20S proteasome together with two 19S regulatory complexes. Alternatively, PA28 complexes can bind to the ends of the 20S proteasome to form PA28-proteasome complexes and PA28-proteasome-19S hybrid complexes have also been described. Immunoproteasome subunits occur in 26S proteasomes as well as in PA28-proteasome complexes. We have found differences in the subcellular distribution of the different forms of proteasomes. The gamma-interferon inducible PA28 alpha and beta subunits are predominantly located in the cytoplasm, while 19S regulatory complexes (present at significant levels only in 26S complexes) are present in the nucleus as well as in the cytoplasm. Immunoproteasomes are greatly enriched at the endoplasmic reticulum (ER) where they may facilitate the generation of peptides for transport into the lumen of the ER. We have also investigated the effects of gamma-interferon on the levels and subcellular distribution of inducible subunits and regulator subunits. In each case gamma-interferon was found to increase the level but not to alter the distribution. Several subunits of proteasomes are phosphorylated including alpha subunits C8 (alpha7) and C9 (alpha3), and ATPase subunit S4 (rpt2). Our studies have shown that gamma-interferon treatment decreases the level of phosphorylation of proteasomes. We have investigated the role of phosphorylation of C8 by casein kinase II by site directed mutagenesis. The results demonstrate that phosphorylation at either one of the two sites is essential for the association of 19S regulatory complexes and that the ability to undergo phosphorylation at both sites gives the most efficient incorporation of C8 into the 26S proteasome.
...
PMID:Regulation of proteasome complexes by gamma-interferon and phosphorylation. 1129 98

Streptococcus pneumoniae is one of the most important human pathogens and improvement of the currently used polysaccharide vaccines is being pursued. We constructed DNA vaccine vectors containing either the full-length psaA (pneumococcal surface adhesin A) or a truncated pspA (pneumococcal surface protein A--pspA') gene. Both constructs showed transient expression of the antigens in vertebrate cells and induced significant antibody response to the pneumococcal antigens in BALB/c mice injected intramuscularly (i.m.). Fusion with an N-terminal cytoplasmatic SV40 T-antigen (CT-Ag), which was previously shown to stabilize poorly expressed antigens through association with Hsp73, also induced anti-PspA antibody response. The induction of antibodies with a low IgG1:IgG2a ratio and elevated gamma interferon (IFN-gamma) production by spleen cells elicited by DNA vaccination indicate preferential priming of Th1 immunity. Since induction of antibodies against both PsaA and PspA was previously shown to correlate with protection against fatal infection with S. pneumoniae and cell-mediated immune responses could contribute to protection, further evaluation of PsaA and PspA as antigens for a DNA vaccine against S. pneumoniae could be promising.
...
PMID:PsaA (pneumococcal surface adhesin A) and PspA (pneumococcal surface protein A) DNA vaccines induce humoral and cellular immune responses against Streptococcus pneumoniae. 1173 44

P58(IPK) was discovered as an inhibitor of the interferon-induced, protein kinase, PKR. Upon virus infection, PKR can, as part of the host defense system, inhibit mRNA translation by phosphorylating the alpha subunit of protein synthesis eukaryotic initiation factor 2 (eIF-2alpha). We previously found that influenza virus recruits the cellular P58(IPK) co-chaperone to inhibit PKR activity and thus facilitate viral protein synthesis. P58(IPK) contains nine tetratricopeptide repeat (TPR) motifs in addition to the highly conserved J domain found in all DnaJ chaperone family members. To define the role of molecular chaperones in regulating cell growth in addition to PKR regulation, we performed a detailed analysis of the P58(IPK) J domain. Using growth rescue assays, we found that the P58(IPK) J domain substituted for the J domains of other DnaJ proteins, including DnaJ in Escherichia coli and Ydj1 in Saccharomyces cerevisiae. This is the first time a cellular J domain from a mammalian DnaJ family member was shown to be functional in both prokaryotic DnaJ and eukaryotic Ydj1 constructs. Furthermore, point mutations within the conserved HPD residue cluster of the P58(IPK) J domain disrupted P58(IPK) J function including stimulation of ATPase activity of Hsp70. However, the P58(IPK) HPD mutants still inhibited PKR activity and thus supported cell growth in a yeast rescue assay. Overexpression of the HPD mutants of P58(IPK), similar to their wild-type counterpart, also stimulated mRNA translation in a mammalian cell system. Taken together, our data necessitate a model of P58(IPK) inhibition of PKR kinase activity and stimulation of mRNA translation, which does not require classical J domain function found in the DnaJ molecular chaperone family.
...
PMID:Inactivation of the PKR protein kinase and stimulation of mRNA translation by the cellular co-chaperone P58(IPK) does not require J domain function. 1193 89

SWI/SNF regulates growth control, differentiation and tumor suppression, yet few direct targets of this chromatin-remodeling complex have been identified in mammalian cells. We report that SWI/SNF is required for interferon (IFN)-gamma induction of CIITA, the master regulator of major histocompatibility complex class II expression. Despite the presence of functional STAT1, IRF-1 and USF-1, activators implicated in CIITA expression, IFN-gamma did not induce CIITA in cells lacking BRG1 and hBRM, the ATPase subunits of SWI/SNF. Reconstitution with BRG1, but not an ATPase-deficient version of this protein (K798R), rescued CIITA induction, and enhanced the rate of induction of the IFN-gamma-responsive GBP-1 gene. Not ably, BRG1 inhibited the CIITA promoter in transient transfection assays, underscoring the importance of an appropriate chromosomal environment. Chromatin immunoprecipitation revealed that BRG1 interacts directly with the endogenous CIITA promoter in an IFN-gamma-inducible fashion, while in vivo DNase I footprinting and restriction enzyme accessibility assays showed that chromatin remodeling at this locus requires functional BRG1. These data provide the first link between a cytokine pathway and SWI/SNF, and suggest a novel role for this chromatin-remodeling complex in immune surveillance.
...
PMID:Interferon-gamma-induced chromatin remodeling at the CIITA locus is BRG1 dependent. 1195 17

Microglial activation is common in several neurodegenerative disorders. In the present study, we used the murine BV-2 microglial cell line stimulated with gamma-interferon and lipopolysaccharide to gain new insights into the effects of endogenously produced NO on mitochondrial respiratory capacity, iron regulatory protein activity, and redox-active iron level. Using polarographic measurement of respiration of both intact and digitonin-permeabilized cells, and spectrophotometric determination of individual respiratory chain complex activity, we showed that in addition to the reversible inhibition of cytochrome-c oxidase, long-term endogenous NO production reduced complex-I and complex-II activities in an irreversible manner. As a consequence, the cellular ATP level was decreased in NO-producing cells, whereas ATPase activity was unaffected. We show that NO up-regulates RNA-binding of iron regulatory protein 1 in microglial cells, and strongly reduces the labile iron pool. Together these results point to a contribution of NO derived from inflammatory microglia to the misregulation of energy-producing reactions and iron metabolism, often associated with the pathogenesis of neurodegenerative disorders.
...
PMID:Impact of endogenous nitric oxide on microglial cell energy metabolism and labile iron pool. 1206 70

Blastocyst formation and expansion are dependent on the differentiation and function of a proper transport of nutrients through the trophectoderm (TE) enclosing the inner cell mass (ICM). Coincident with compaction and cavitation, glucose becomes the preferred energy substrate of the early embryo. These hallmarks in early development require well-orchestrated gene expression patterns specifically with regard to timing and localization. The present study investigated the relative abundance (RA) of gene transcripts in the two lineages of in vitro-produced expanded bovine blastocysts in relation to timing of development, i.e., blastocyst expansion and localization of specific mRNAs. Expanded blastocysts from either Day 7 or Day 8 or isolated ICMs derived thereof were analyzed with the aid of a semiquantitative reverse transcriptase-polymerase chain reaction assay for gene transcripts, which are thought to play a pivotal role in blastocyst expansion, i.e., Na/K-ATPase alpha1 subunit (Na/K), E-cadherin (E-cad), zonula occludens protein-1 (ZO-1), desmocollin II (Dc II), plakophilin (Plako), trophoblastic function (interferon tau [IFtau]), and glucose transport (glucose transporter-1, -3, -4 [Glut-1, -3, -4]). Total cell number, ICM cell number, or ICM/total cells ratio were similar in Day 7 and Day 8 expanded blastocysts. Significant differences were determined in the RA for Na/K, E-cad, Dc II, Plako, and ZO-1 transcripts between TE cells of expanded blastocysts derived from either Day 7 or Day 8. The RA of Dc II, Glut-1, and Glut-4 was significantly decreased in the ICM compared with the TE at Day 7. Similarly, the RA of Na/K, Dc II, Glut-1, and Glut-4 at Day 8 of development was significantly decreased in the ICM compared with the TE. Interestingly, no differences were observed when comparing ICMs originating from blastocysts expanded at either Day 7 or Day 8. Plako and IFtau transcripts were not detected in isolated ICMs, indicating that expression of these mRNAs is restricted to the TE. In contrast, similar expression patterns within the ICM and TE were determined for Na/K, E-cad, ZO-1, and Glut-3 mRNA. Dc II, Glut-1, and Glut-4 were more abundant in the TE than in ICM. Results show that expression of developmentally important genes is related to the two cell lineages in the early embryo and emphasize the critical role of a well controlled spatial gene expression pattern for regular preimplantation development.
...
PMID:Timing of blastocyst expansion affects spatial messenger RNA expression patterns of genes in bovine blastocysts produced in vitro. 1260 28

The objective of this study was to compare the relative transcript abundance of several important candidate genes between ovine and bovine blastocysts. Blastocysts were produced by in vitro maturation, fertilization, and subsequent culture in one of two formulations of synthetic oviduct fluid medium (SOF1 and SOF2). From each IVF replicate groups of 10 bovine and 10 ovine blastocysts from each of the two media were used for analysis of mRNA relative abundance. Transcript levels for mitochondrial Mn-superoxide dismutase (MnSOD), survivin, and glucose transport 5 (Glut-5) were significantly higher in ovine blastocysts than bovine (P < 0.05), while transcripts for Connexin 31 (Cx31), interferon tau (IFN-tau), and sarcosine oxidase (SOX) were significantly more abundant in bovine blastocysts (P < 0.01). For the two remaining transcripts, E-cadherin (E-cad) and Na/K ATPase (Na/K), there was no difference. Culture of bovine embryos in SOF2 resulted in a significant increase in the level of expression of MnSOD and Glut-5 (P < 0.05) compared to those bovine embryos cultured in SOF1. For all the other transcripts, except survivin, there was a significant decrease in the relative abundance. Culture of sheep embryos in either SOF1 or SOF2 did not have a major influence on transcript abundance; of the eight transcripts examined, the relative abundance of only one, SOX, was significantly altered. Bovine blastocysts produced in SOF2 had significantly higher survival rates at 24, 48, and 72 hr and significantly higher hatching rates following vitrification and warming than those cultured in SOF1 (P < 0.001). In conclusion, we have quantified for the first time the mRNA expression of a set of important developmental genes in sheep blastocysts and we have demonstrated that these differences between species in their adaptability to culture conditions, manifested in differences in embryo morphology and cryotolerance, are related to differences in mRNA relative abundance. The results also highlight the usefulness of transcript analysis as a marker of embryo quality.
...
PMID:Species-related differences in blastocyst quality are associated with differences in relative mRNA transcription. 1545 17

Cytokines and free radicals are mediators of beta-cell death in type 1 diabetes. Under in vitro conditions, interleukin-1beta (IL-1beta) + gamma-interferon (IFN-gamma) induce nitric oxide (NO) production and apoptosis in rodent and human pancreatic beta-cells. We have previously shown, by microarray analysis of primary beta-cells, that IL-1beta + IFN-gamma decrease expression of the mRNA encoding for the sarcoendoplasmic reticulum pump Ca(2+) ATPase 2b (SERCA2b) while inducing expression of the endoplasmic reticulum stress-related and proapoptotic gene CHOP (C/EBP [CCAAT/enhancer binding protein] homologous protein). In the present study we show that cytokine-induced apoptosis and necrosis in primary rat beta-cells and INS-1E cells largely depends on NO production. IL-1beta + IFN-gamma, via NO synthesis, markedly decreased SERCA2b protein expression and depleted ER Ca(2+) stores. Of note, beta-cells showed marked sensitivity to apoptosis induced by SERCA blockers, as compared with fibroblasts. Cytokine-induced ER Ca(2+) depletion was paralleled by an NO-dependent induction of CHOP protein and activation of diverse components of the ER stress response, including activation of inositol-requiring ER-to-nucleus signal kinase 1alpha (IRE1alpha) and PRK (RNA-dependent protein kinase)-like ER kinase (PERK)/activating transcription factor 4 (ATF4), but not ATF6. In contrast, the ER stress-inducing agent thapsigargin triggered these four pathways in parallel. In conclusion, our results suggest that the IL-1beta + IFN-gamma-induced decrease in SERCA2b expression, with subsequent depletion of ER Ca(2+) and activation of the ER stress pathway, is a potential contributory mechanism to beta-cell death.
...
PMID:Cytokines downregulate the sarcoendoplasmic reticulum pump Ca2+ ATPase 2b and deplete endoplasmic reticulum Ca2+, leading to induction of endoplasmic reticulum stress in pancreatic beta-cells. 1567 3


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---