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At least 199 records · Page 11Linked to original sources
PubMed1999

The structural basis for complement receptor type 2 (CR2, CD21)-mediated alternative pathway activation of complement: studies with CR2 deletion mutants and vaccinia virus complement-control protein-CR2 chimeras.

The role of complement receptor 2 (CR2) short consensus repeats (SCR) in binding of hydrolyzed C3 (iC3) to form an alternative pathway (AP) convertase, and promoting C3 fragment deposition following AP activation, was examined. We used (1) K562 cells transfected with CR2 constructs, where the C3d-binding site of CR2 (SCR1+2) was replaced with the four-SCR vaccinia virus complement control protein (VCP), or truncation mutants thereof, and (2) COS cells transfected with wild-type (wt) CR2, or deletion mutants thereof. AP activation required iC3 binding in both systems. Thus, the VCP-CR2 chimera had an iC3 binding efficiency of 11.4 %, compared to wtCR2, and a relative AP activity of 5.5 %, the truncation mutants being inactive. Of the CR2 mutants, only EK (DeltaSCR10 - 11) had AP activity similar to wtCR2. NN (DeltaSCR6 - 8) and NOP (DeltaSCR6-mid14) had reduced AP activity, but near normal iC3 binding. XB (DeltaSCR3 - 6) and PP (DeltaSCR3-mid14) were inactive in both assays. We conclude that, whilst iC3 binding to CR2 via SCR1 - 4 is essential for AP activation, the efficiency of C3 deposition also depends on the midportion of CR2.

Animals↗
PubMed1982

Malignant pheochromocytoma. Severe clinical exacerbation and release of stored catecholamines during lymphoma chemotherapy.

The association of malignant pheochromocytoma and poorly differentiated lymphocytic lymphoma has not previously been reported. A case is presented of a 58-year old man with a 20-year history of malignant pheochromocytoma well controlled on Dibenzyline who was found to have poorly differentiated lymphocytic lymphoma. During lymphoma chemotherapy with cyclophosphamide, vincristine and prednisone (VCP) he developed tachycardia and syncope accompanied by severe hypertension. During the next course of chemotherapy one month later, 24-hour urinary VMA, metanephrine and catecholamine values were determined before, during and after the chemotherapy and were found to have increased two- to ten-fold. This suggests that VCP caused tumor lysis with release of catecholamines into the circulation.

Adrenal Gland Neoplasms↗
PubMed1995

The higher plant Arabidopsis thaliana encodes a functional CDC48 homologue which is highly expressed in dividing and expanding cells.

We have identified an Arabidopsis thaliana CDC48 gene which, unlike the putative mammalian homologue vasolin-containing protein (VCP), functionally complements Saccharomyces cerevisiae cdc48 mutants. CDC48 is an essential gene in S. cerevisiae and genetic studies suggest a role in spindle pole body separation. Biochemical studies link VCP function to membrane trafficking and signal transduction. We have described the AtCDC48 expression pattern in a multicellular eukaryote; the zones of cell division, expansion and differentiation are physically separated in higher plants, thus allowing the analysis of in situ expression patterns with respect to the state of cell proliferation. AtCDC48 is highly expressed in the proliferating cells of the vegetative shoot, root, floral inflorescence and flowers, and in rapidly growing cells. AtCDC48 mRNA and the encoded protein are up-regulated in the developing microspores and ovules. AtCDC48 expression is down-regulated in most differentiated cell types. AtCDC48p was primarily localized to the nucleus and, during cytokinesis, to the phragmoplast, a site where membrane vesicles are targeted in the deposition of new cell wall materials. This study shows that the essential cell division function of CDC48 has been conserved by, at least, some multicellular eukaryotes and suggests that in higher plants, CDC48 functions in cell division and growth processes.

Adenosine Triphosphatases↗
PubMed1997

NVL: a new member of the AAA family of ATPases localized to the nucleus.

We report the cloning of NVL, a newly recognized human gene that encodes an approximately 110-kDa nuclear protein designated NVLp (nuclear VCP-like protein), which is a member of a rapidly growing family of ATP-binding proteins recently denoted the AAA family (ATPases associated with diverse cellular activities) (W. H. Kunau et al., 1993, Biochimie 75:209-224). NVL was isolated by degenerate PCR using oligonucleotides corresponding to the yeast PEX1 gene, which is necessary for peroxisomal biogenesis. Two cDNAs, designated NVL.1 and NVL.2, may represent alternatively spliced forms of a single gene that maps to chromosome 1q41-q42.2. NVL has greatest similarity to the VCP subfamily of AAA proteins, is widely expressed, and encodes a nuclear protein with two highly similar ATP-binding domains. We speculate that NVLp is involved in an ATP-dependent nuclear process.

Adenosine Triphosphatases↗
PubMed1997

The cowpox virus-encoded homolog of the vaccinia virus complement control protein is an inflammation modulatory protein.

Vaccinia virus complement control protein (VCP) is encoded by vaccinia virus, with its homolog encoded by other pathogenic poxviruses including variola virus. Since rodents are the primary reservoir hosts of cowpox virus (CPV) and since CPV encodes a highly conserved functional homolog of VCP, termed here the inflammation modulatory protein (IMP), the effects of injection of CPV into the footpads of mice was determined in order to study the precise in vivo effects of IMP. Macroscopic examination of the site of injection with a recombinant virus lacking IMP (CPV-IMP) showed greater tissue damage, with more hemorrhage and induration, than sites injected with the wild-type cowpox virus. In addition, the measurement of the specific swelling response carried out for several weeks revealed significantly greater swelling in mice injected with CPV-IMP. Thus, IMP modulates the complement-activated inflammatory response in vivo. Furthermore, the diminished destruction of host tissue observed in the presence of IMP indicates symbiosis in which the virus ensures the preservation of surrounding host tissue, possibly to support the growth of its progeny.

Amino Acid Sequence↗
PubMed1992

Cerebral blood flow fluctuation in low-risk preterm newborns.

Cerebral blood flow (CBF) fluctuation was studied by analyzing Doppler internal carotid blood velocity recordings of 13 healthy preterm newborns obtained in the course of their first 5 days of life. As measures of fluctuation we used the interquartile range (IQR) and the coefficient of variation (CV) of the ensemble of heart beats of a 20-s recording. In this way we determined fluctuation of the following velocity curve parameters (VCPs): end diastolic velocity; mean velocity; peak systolic velocity and pulsatility index (PI). The pooled data 5-95% intervals for fluctuation thus measured, were: 93-281% for CV; 0.6-3.7 cm/s for the IQR of the velocities; and 4-19% for the PI-IQR. Multiple regression analysis of IQR revealed significant relationships with: the VCP level; with restlessness; and with patency of the ductus arteriosus. Our findings imply that: (1) CBF has various qualities with different stability, mean velocity being the most stable; (2) for all the VCPs investigated, fluctuation is physiological in the early days after preterm birth; (3) most likely, there exists no age trend; (4) restlessness rather than wakefulness, enhances fluctuation; (5) patent ductus arteriosus destabilizes CBF; and (6) for a proper insight into fluctuation, the level of the VCP in question must be taken into account. We suggest that, the enhancing effect that patent ductus arteriosus has on fluctuation pays a contribution to the pathogenesis of brain damage. Finally, we conclude that the IQR represents fluctuation better than does the more commonly used CV.

Blood Flow Velocity↗
PubMed2005

Evolutionary history of orthopoxvirus proteins similar to human complement regulators.

Orthopoxviruses include many important pathogens such as variola major virus, camelpox, buffalopox, monkeypox, cowpox, and variola minor viruses. This group of viruses also includes vaccinia virus, which is extensively used in human vaccine development. Genomes of orthopoxviruses encode proteins with sequences similar to human regulators of complement activation (RCA) that contain tandem short consensus repeats (SCRs). We employed phylogenetic tree analysis to evaluate the structural relationships among SCRs of orthopoxvirus RCA-like proteins and those of human complement regulators. The human complement RCA proteins analyzed were factor H (FH), C4 binding protein alpha chain, membrane cofactor protein (MCP), decay accelerating factor (DAF), and complement receptors type 1 (CR1) and 2 (CR2). Sequences of key poxvirus regulators of complement activation, vaccinia virus complement control protein (VCP), smallpox inhibitor of complement enzymes (SPICE), and cowpox inflammation modulatory protein (IMP) were similar to SCRs 1 through 5 of C4 binding protein, alpha chain, and they were also clustered with other homologous repeats of MCP, DAF, CR1, CR2, and FH. Phylogenetic clustering of RCA sequences suggested that poxvirus complement regulators VCP, SPICE, and IMP arose from a single ancestral sequence that shared similarity with all human regulators of complement activation. Any changes in poxvirus complement regulators leading to the enhancement of their ability to regulate complement activation likely resulted from new mutations in the viral lineages.

Antigens, CD↗
PubMed2003

Prolonged retention of vaccinia virus complement control protein following IP injection: implications in blocking xenorejection.

The vaccinia virus complement control protein (VCP) blocks classic and alternate complement pathways by binding to the third and fourth complement components and by blocking the formation of the C3-convertase as well as by accelerating the decay of the C3 and C4 convertase. The therapeutic potential of VCP has been extensively studied for brain injury, xenotransplantation, Alzheimer's disease, and spinal cord injury. We investigated the pharmacokinetic behavior of rVCP in mice. Dosage of rVCP was studied by injecting different concentrations of rVCP. A 25 mg/kg or greater dose injected intraperitoneally was found to be adequate to suppress complement for more than 8 hours.

Animals↗
PubMed2001

Molecular characterisation of mitochondrial and cytosolic trypanothione-dependent tryparedoxin peroxidases in Trypanosoma brucei.

In trypanosomatids, removal of hydrogen peroxide and other aryl and alkyl peroxides is achieved by the NADPH-dependent trypanothione peroxidase system, whose components are trypanothione reductase (TRYR), trypanothione, tryparedoxin (TRYX) and tryparedoxin peroxidase (TRYP). Here, we report the cloning of a multi-copy tryparedoxin peroxidase gene (TRYP1) from Trypanosoma brucei brucei encoding a protein with two catalytic VCP motifs similar to the cytosolic TRYP from Crithidia fasciculata. In addition, we characterise a novel single copy gene encoding a second tryparedoxin peroxidase (TRYP2). TRYP2 shows 51% similarity to TRYP1, possesses a putative mitochondrial import sequence at its N-terminus and has a variant IPC motif replacing the second VCP motif implicated in catalysis in other 2-Cys peroxiredoxins. TRYP1 and TRYP2 were expressed in Escherichia coli, and the purified recombinant proteins shown to utilise hydrogen peroxide in the presence of NADPH, trypanothione, TRYR and TRYX from T. brucei, similar to the C. fasciculata cytoplasmic system. Western blots showed that TRYX, TRYP1 and TRYP2 are expressed in both bloodstream and procyclic forms of the life cycle. To determine the precise localisation of TRYX, TRYP1 and TRYP2 in the parasite, polyclonal antibodies to purified recombinant TRYX and TRYP1 and monoclonal antibody to TRYP2 were generated in mice. In-situ immunofluorescence and immunoelectron microscopy revealed a colocalisation of TRYX and TRYP1 in the cytosol, whereas TRYP2 was principally localised in the mitochondrion.

Amino Acid Sequence↗
PubMed1999

Synergistic roles for Pim-1 and c-Myc in STAT3-mediated cell cycle progression and antiapoptosis.

The activation of STAT3 by the cytokine receptor gp130 is required for both the G1 to S cell cycle transition and antiapoptosis. We found that Pim-1 and Pim-2 are targets for the gp130-mediated STAT3 signal. Expression of a kinase-defective Pim-1 mutant attenuated gp130-mediated cell proliferation. Constitutive expression of Pim-1 together with c-myc, another STAT3 target, fully compensated for loss of the STAT3-mediated cell cycle progression, antiapoptosis, and bcl-2 expression. We also identified valosine-containing protein (VCP) as a target gene for the Pim-1-mediated signal. Expression of a mutant VCP led cells to undergo apoptosis. These results indicate that Pim-family proteins play crucial roles in gp130-mediated cell proliferation and explain the synergy between Pim and c-Myc proteins in cell proliferation and lymphomagenesis.

Adenosine Triphosphatases↗
PubMed2003

Variola virus immune evasion proteins.

Variola virus, the causative agent of smallpox, encodes approximately 200 proteins. Over 80 of these proteins are located in the terminal regions of the genome, where proteins associated with host immune evasion are encoded. To date, only two variola proteins have been characterized. Both are located in the terminal regions and demonstrate immunoregulatory functions. One protein, the smallpox inhibitor of complement enzymes (SPICE), is homologous to a vaccinia virus virulence factor, the vaccinia virus complement-control protein (VCP), which has been found experimentally to be expressed early in the course of vaccinia infection. Both SPICE and VCP are similar in structure and function to the family of mammalian complement regulatory proteins, which function to prevent inadvertent injury to adjacent cells and tissues during complement activation. The second variola protein is the variola virus high-affinity secreted chemokine-binding protein type II (CKBP-II, CBP-II, vCCI), which binds CC-chemokine receptors. The vaccinia homologue of CKBP-II is secreted both early and late in infection. CKBP-II proteins are highly conserved among orthopoxviruses, sharing approximately 85% homology, but are absent in eukaryotes. This characteristic sets it apart from other known virulence factors in orthopoxviruses, which share sequence homology with known mammalian immune regulatory gene products. Future studies of additional variola proteins may help illuminate factors associated with its virulence, pathogenesis and strict human tropism. In addition, these studies may also assist in the development of targeted therapies for the treatment of both smallpox and human immune-related diseases.

Animals↗
PubMed2005

Structural basis for antagonism by suramin of heparin binding to vaccinia complement protein.

Suramin is a competitive inhibitor of heparin binding to many proteins, including viral envelope proteins, protein tyrosine phosphatases, and fibroblast growth factors (FGFs). It has been clinically evaluated as a potential therapeutic in treatment of cancers caused by unregulated angiogenesis, triggered by FGFs. Although it has shown clinical promise in treatment of several cancers, suramin has many undesirable side effects. There is currently no experimental structure that reveals the molecular interactions responsible for suramin inhibition of heparin binding, which could be of potential use in structure-assisted design of improved analogues of suramin. We report the structure of suramin, in complex with the heparin-binding site of vaccinia virus complement control protein (VCP), which interacts with heparin in a geometrically similar manner to many FGFs. The larger than anticipated flexibility of suramin manifested in this structure, and other details of VCP-suramin interactions, might provide useful structural information for interpreting interactions of suramin with many proteins.

Binding Sites↗
PubMed2006

Mechanisms of disease: genetics of Paget's disease of bone and related disorders.

Paget's disease of bone (PDB) is a common disorder in which focal abnormalities of increased bone turnover lead to complications such as bone pain, deformity, pathological fractures, and deafness. PDB has a strong genetic component and several susceptibility loci for the disease have been identified by genome-wide scans. Mutations that predispose individuals to PDB and related disorders have been identified in four genes. The rare PDB-like syndromes of familial expansile osteolysis, early-onset familial PDB, and expansile skeletal hyperphosphatasia are caused by insertion mutations in TNFRSF11A, which encodes receptor activator of nuclear factor (NF)kappaB (RANK)-a critical regulator of osteoclast function. Inactivating mutations in TNFRSF11B, which encodes osteoprotegerin (a decoy receptor for RANK ligand) cause idiopathic hyperphosphatasia, and polymorphisms in this gene seem to increase the risk for classical PDB. Mutations of the sequestosome 1 gene (SQSTM1), which encodes an important scaffold protein in the NFkappaB pathway, are a common cause of classical PDB. The rare syndrome of hereditary inclusion body myopathy, PDB, and fronto-temporal dementia is caused by mutations in the valosin-containing protein (VCP) gene. This gene encodes VCP, which has a role in targeting the inhibitor of NFkappaB for degradation by the proteasome. Several additional genes for PDB remain to be discovered, and it seems likely that they will also involve the RANK-NFkappaB signaling pathway or components of the proteasomal processing of this pathway, underscoring the critical importance of this signaling pathway in bone metabolism and bone disease.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Cross-calibration of GE/Lunar pencil and fan-beam dual energy densitometers--bone mineral density and body composition studies.

OBJECTIVE: In vitro and in vivo comparisons of bone mineral density (BMD) and body composition between GE/Lunar pencil (DPXL) and fan-beam (PRODIGY) absorptiometers. DESIGN: Comparison of BMD, bone mineral content (BMC) and area of lumbar spine (L2-L4), femoral neck and total body. Total body composition compartments tissue (TBTissue), fat (TBF), lean tissue (TBLean) and %TBF were also compared. SETTING: Centre for Bone and Body Composition Research, University of Leeds. PHANTOMS/SUBJECTS: A range of spine phantoms, a variable composition phantom (VCP) and total body phantom. A total of 72 subjects were included for the in vivo study. RESULTS: In vitro: A small significant underestimation of BMD by the Prodigy compared to the DPXL ranging from 0.7 to 2% (p<0.05-0.001) for the spine phantoms. The Prodigy underestimated the VCP %Fat. Although the Prodigy underestimated phantom TBBMD by 1.1+/-1.0%, TBBMC and area were reduced by 8.2+/-1.4 and 7.3+/-1.0%, respectively. The Prodigy overestimated TBTissue 1508 g (2.2%), TBLean 588 g (1.2%), TBF 919 g (4.8%) and %TBF (0.8%). In vivo: BMD cross-calibration was only required in the femoral neck, DPXL(BMD)=0.08+0.906*PRODIGY(BMD). The Prodigy had higher estimates for TBTissue 1360 g (2.3%), TBLean 840 g (2.0%), TBF 519 g (3.4%), TBBMC 32.8 g (1.3%) and %TBF (0.3%). Cross-calibration equations were required for TBTissue(DPXL)=-1158+0.997*TBTissue(PRODIGY) and TBBMC(DPXL)= 89.7+0.949*TBBMC(PRODIGY). CONCLUSIONS: Small differences between the two absorptiometers for both BMD and body composition can be made compatible by use of cross-calibration equations and factors. The discrepancy in body composition compartments requires further research.

Absorptiometry, Photon↗
PubMed2005

Genetics of Paget's disease of bone.

PDB (Paget's disease of bone) is a common condition characterized by focal increases in bone turnover affecting one or more sites throughout the skeleton. Genetic factors are important in the pathogenesis of PDB and many families have been described where PDB is inherited in an autosomal-dominant fashion. Several candidate loci for susceptibility to PDB and related syndromes have been identified by genome-wide scans and recent evidence suggests that mutations in genes that encode components of the RANK [receptor activator of NF-kappaB (nuclear factor-kappaB)]/NF-kappaB signalling pathway play an important role in the pathogenesis of this group of diseases. Insertion mutations in the TNFRSF11A gene encoding RANK have been identified as the cause of familial expansile osteolysis, some cases of early onset PDB and expansile skeletal hyperphosphatasia. Inactivating mutations in the TNFRSF11B gene that encodes OPG (osteoprotegerin) have been found to cause the syndrome of juvenile PDB. Polymorphisms in OPG also appear to increase the risk of developing PDB. The most important causal gene for classical PDB is Sequestosome 1 (SQSTM1), which is a scaffold protein in the NF-kappaB signalling pathway, and mutations affecting the UBA (ubiquitin-associated) domain of this protein occur in between 20-50% of familial and 10-20% of sporadic PDB cases. The rare syndrome of IBMPFD (inclusion body myopathy, PDB and fronto-temporal dementia) is due to mutations in the VCP gene and these also cluster in the domain of VCP that interacts with ubiquitin, suggesting a common disease mechanism with SQSTM1-mediated PDB.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Resolution of vulvitis circumscripta plasmacellularis with topical imiquimod: two case reports.

Vulvitis circumscripta plasmacellularis (VCP) is a rare but well-described entity. It is notorious for its recalcitrant nature to various modalities of treatment. Intralesional interferon-alpha showed some promise, with complete resolution, but is coupled with the side-effect of myelosuppression. Topical imiquimod is a novel immune response modifier with the ability to induce the production of interferon-alpha. In this paper, we report two cases of VCP whose lesions were resistant to antibiotics, topical and oral corticosteroids, but resolved after a treatment trial with imiquimod.

Adjuvants, Immunologic↗
PubMed2005

Recruitment of the p97 ATPase and ubiquitin ligases to the site of retrotranslocation at the endoplasmic reticulum membrane.

Misfolded proteins are eliminated from the endoplasmic reticulum (ER) by retrotranslocation into the cytosol, a pathway hijacked by certain viruses to destroy MHC class I heavy chains. The translocation of polypeptides across the ER membrane requires their polyubiquitination and subsequent extraction from the membrane by the p97 ATPase [also called valosin-containing protein (VCP) or, in yeast, Cdc48]. In higher eukaryotes, p97 is bound to the ER membrane by a membrane protein complex containing Derlin-1 and VCP-interacting membrane protein (VIMP). How the ubiquitination machinery is recruited to the p97/Derlin/VIMP complex is unclear. Here, we report that p97 interacts directly with several ubiquitin ligases and facilitates their recruitment to Derlin-1. During retrotranslocation, a substrate first interacts with Derlin-1 before p97 and other factors join the complex. These data, together with the fact that Derlin-1 is a multispanning membrane protein forming homo-oligomers, support the idea that Derlin-1 is part of a retrotranslocation channel that is associated with both the polyubiquitination and p97-ATPase machineries.

Adenosine Triphosphatases↗
PubMed2004

Structure of the N-terminal domain of PEX1 AAA-ATPase. Characterization of a putative adaptor-binding domain.

Peroxisomes are responsible for several pathways in primary metabolism, including beta-oxidation and lipid biosynthesis. PEX1 and PEX6 are hexameric AAA-type ATPases, both of which are indispensable in targeting over 50 peroxisomal resident proteins from the cytosol to the peroxisomes. Although the tandem AAA-ATPase domains in the central region of PEX1 and PEX6 are highly similar, the N-terminal sequences are unique. To better understand the distinct molecular function of these two proteins, we analyzed the unique N-terminal domain (NTD) of PEX1. Extensive computational analysis revealed weak similarity (<10% identity) of PEX1 NTD to the N-terminal domains of other membrane-related type II AAA-ATPases, such as VCP (p97) and NSF. We have determined the crystal structure of mouse PEX1 NTD at 2.05-A resolution, which clearly demonstrated that the domain belongs to the double-psi-barrel fold family found in the other AAA-ATPases. The N-domains of both VCP and NSF are structural neighbors of PEX1 NTD with a 2.7- and 2.1-A root mean square deviation of backbone atoms, respectively. Our findings suggest that the supradomain architecture, which is composed of a single N-terminal domain followed by tandem AAA domains, is a common feature of organellar membrane-associating AAA-ATPases. We propose that PEX1 functions as a protein unfoldase in peroxisomal biogenesis, using its N-terminal putative adaptor-binding domain.

ATPases Associated with Diverse Cellular Activitie↗