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PubMed2006

Ataxin-3 binds VCP/p97 and regulates retrotranslocation of ERAD substrates.

Expansion of a polyglutamine tract in ataxin-3 (AT3) results in spinocerebellar ataxia type 3/Machado-Joseph disease, one of the nine polyglutamine neurodegenerative diseases. Understanding the normal functions of AT3 as well as its function in the context of expansion of the polyglutamine tract is critical for understanding the disease process. AT3 is a deubiquitylating enzyme with limited information on its cellular functions. We find that transfecting cells with AT3 increases cellular levels of endoplasmic reticulum-associated degradation (ERAD) substrates, CD3delta and TCRalpha, but does not alter levels of several non-ERAD substrates. AT3 increases the level of CD3delta by decreasing its degradation; pathogenic AT3 decreases degradation to a greater extent than wild-type AT3. Knock-down of endogenous AT3 decreases levels of CD3delta, suggesting that a normal function of AT3 is to regulate levels of ERAD substrates. AT3 binds VCP/p97, a key protein responsible for extracting ERAD substrates from the ER; binding is modulated by the size of the polyglutamine tract, and mutating a sequence adjacent to the polyglutamine tract inhibits the AT3-VCP interaction and AT3-dependent accumulation of CD3delta. AT3 and Ufd1 bind VCP in a mutually exclusive manner; AT3 decreases the interaction of VCP with Ufd1 as well as with ubiquitylated proteins. Using a reconstituted system, AT3 inhibits retrotranslocation of an ERAD substrate from the ER. These data suggest that a normal function of AT3 is to regulate flow through the ERAD pathway by modulating VCP-dependent extraction of proteins from the ER.

Adenosine Triphosphatases↗
PubMed1992

Regulation of complement activity by vaccinia virus complement-control protein.

A major protein secreted by vaccinia virus-infected cells has structural similarity to the super-family of complement-control proteins. This vaccinia complement-control protein (VCP) was studied to determine how it regulates complement activation. VCP was bound by C4b and C3b and served as a cofactor with factor I in cleaving these two molecules. VCP inhibited the formation and accelerated the decay of the classical C3 convertase. It also accelerated decay of the alternative pathway convertase, although higher concentrations were apparently needed. In vitro, therefore, VCP interfered with the classical and alternative complement pathways at several steps. In vivo, this interference may increase the virulence of vaccinia virus by enabling it to escape attack by the host's complement system.

Complement Activation↗
PubMed2001

Deterioration of balance control after limb-saving surgery.

OBJECTIVE: Evaluation of the changes in balance control observed in patients after limb-saving surgery for malignant tumors of the lower limb. DESIGN: Case series. RESULTS: In 11 patients who underwent limb-saving surgery and 10 healthy, age-matched controls, displacement of the amplitude of the center of pressure (ACP) and velocity of the center of pressure (VCP) during normal standing and standing on a balance board were registered. Adding such constraints as standing with eyes closed and performing a Stroop task made standing more complex. During normal standing and on the balance board, both groups showed comparable ACP and VCP values. With eyes closed, both patients and controls showed a higher amplitude and velocity in the anterior-posterior direction. In the patient group, the Stroop task affected the ACP (4.5 +/- 0.8 mm) compared with normal standing (2.9 +/- 0.4 mm) and VCP (18.6 +/- 3.0 mm/sec) compared with normal standing (11.9 +/- 1.0 mm/sec). During balance board standing, the authors found a difference in the VCP for both groups whose eyes were closed and who performed under dual-task conditions (controls, 23.2 +/- 3.3 and 14.9 +/- 2.9 mm/sec; patients, 80.1 +/- 12.9 and 23.6 +/- 3.4 mm/sec). CONCLUSIONS: Although the patient group showed impressive upright standing after limb-saving surgery, upright standing become more difficult under higher visual and cognitive loads. This finding indicates that the level of postural automatism is not complete in these patients.

Adolescent↗
PubMed2005

Influence of aging and sex on voice parameters in patients with unilateral vocal cord paralysis.

OBJECTIVES: The objective of this study was to investigate influences of aging and sex on different voice parameters in patients with unilateral vocal cord paralysis (VCP). STUDY DESIGN: Retrospective review of patients with unilateral VCP. MATERIALS AND METHODS: Forty-seven patients, 22 males, 25 females (24-85 years), were enrolled in the study. The diagnosis of VCP was established by videolaryngostroboscopy. The acoustic parameters of jitter, shimmer, degree of subharmonic, noise to harmonic ratio, fundamental frequency, and maximal intensity were measured. The auditive voice analysis included roughness, breathiness, and hoarseness. Statistical analysis involves Pearson's bivariate correlation coefficients and two-way analysis of variance with interaction variables. RESOLUTION: After unilateral VCP in the elderly, some sex- and age-related differences in the restriction of the voice can be documented. CONCLUSION: In general, the investigated voice parameters showed similar tendencies to those in otherwise healthy aging persons.

Adult↗
PubMedDate not supplied

Autosomal dominant inclusion body myopathy, Paget disease of bone, and frontotemporal dementia.

Autosomal dominant proximal limb girdle or inclusion body myopathy, associated with Paget disease of bone and frontotemporal dementia (IBMPFD) is a recently described disorder that maps to chromosome 9p21.1-p12. We refined the critical locus and identified the gene as the Valosin Containing Protein (VCP) gene, a member of the AAA-ATPase superfamily using a candidate gene approach. Six missense mutations were found to co-segregate with affected individuals only, two of these representing mutation hot spots. We report the clinical and molecular findings in 99 individuals in 13 families. VCP is associated with a variety of cellular activities, including the control of cell cycle, membrane fusion, and the ubiquitin-proteasome degradation pathway. Previous studies have associated VCP mutants in cell lines with vacuole formation and aggregate formation. Identification of VCP as the gene causing IBMPFD has important implications for understanding the pathogenesis of neurodegenerative disorders.

Adenosine Triphosphatases↗
PubMed2002

Potential intervention by vaccinia virus complement control protein of the signals contributing to the progression of central nervous system injury to Alzheimer's disease.

Traumatic brain injury (TBI) is one of the few known risk factors for Alzheimers disease (AD) and for depression. The mechanisms by which trauma causes delayed cognitive deficits are largely unknown. In recent studies, it was demonstrated that the complement system (an important component of the immune system and a mediator of inflammation) is activated both in human AD and following experimental TBI in rats. Amyloid proteins are also present in AD and following TBI, and are known to activate complement in vitro. Based on these and other previous studies, it was hypothesized that regulation of the complement system will attenuate the long-term consequences of TBI. Vaccinia virus complement control protein (VCP) is a protein encoded by vaccinia virus. It blocks both the classic and alternative pathways of complement activation in vitro, and by doings so prevents the generation of proinflammatory chemotactic factors. Based on in vitro studies VCP can block the complement activation by the amyloid beta peptide. Using a fluid percussion rat model that causes traumatic brain injury (TBI), it was found that VCP significantly enhances functional recovery as determined by the Morris Water Maze test. Taken togther these studies indicate that potentially VCP could block molecular signals such as the formation of amyloid beta or the activation of complement to inhibit formation of AD following TBI.

Alzheimer Disease↗
PubMed2005

Identification of complement regulatory domains in vaccinia virus complement control protein.

Vaccinia virus encodes a homolog of the human complement regulators named vaccinia virus complement control protein (VCP). It is composed of four contiguous complement control protein (CCP) domains. Previously, VCP has been shown to bind to C3b and C4b and to inactivate the classical and alternative pathway C3 convertases by accelerating the decay of the classical pathway C3 convertase and (to a limited extent) the alternative pathway C3 convertase, as well as by supporting the factor I-mediated inactivation of C3b and C4b (the subunits of C3 convertases). In this study, we have mapped the CCP domains of VCP important for its cofactor activities, decay-accelerating activities, and binding to the target proteins by utilizing a series of deletion mutants. Our data indicate the following. (i) CCPs 1 to 3 are essential for cofactor activity for C3b and C4b; however, CCP 4 also contributes to the optimal activity. (ii) CCPs 1 to 2 are enough to mediate the classical pathway decay-accelerating activity but show very minimal activity, and all the four CCPs are necessary for its efficient activity. (iii) CCPs 2 to 4 mediate the alternative pathway decay-accelerating activity. (iv) CCPs 1 to 3 are required for binding to C3b and C4b, but the presence of CCP 4 enhances the affinity for both the target proteins. These results together demonstrate that the entire length of the protein is required for VCP's various functional activities and suggests why the four-domain structure of viral CCP is conserved in poxviruses.

CD55 Antigens↗
PubMed1984

Localization of the cerebroventricular receptors involved in CNS-induced natriuresis.

Ventriculocisternal perfusion (VCP) or localized "push-pull" perfusion (PPP) was performed in pentobarbital-anesthetized dogs. Renal function was studied in protocols consisting of a 1-h experimental period bracketed by 1-h control and recovery periods. The animals were perfused with artificial cerebral spinal fluid (CSF) throughout the protocol but the sodium concentration was elevated (300 mM, high Na) during the experimental period. In the first series of experiments, prior to VCP, petroleum jelly plugs were injected into either the ventral third ventricle (V3V) or other brain regions. When petroleum jelly plugs were injected into the V3V prior to VCP, they prevented perfusates from reaching this area, as determined by subsequent dye perfusion. These V3V plugs blocked the natriuresis and ADH response otherwise induced by high Na VCP. In the second series of experiments, the anterior portion of the V3V (AV3V) was perfused by means of PPP. In some of the PPP experiments a V3V plug was also injected to ensure restriction of the stimulus to the AV3V. PPP of the AV3V with high Na CSF at 50 microliter/min did not induce a natriuresis (either with or without a V3V plug). However, when the high Na CSF was perfused at a very high rate (100 microliter/min) and the stimulus was not restricted to the AV3V by a V3V plug, a natriuresis did occur. These results suggest that the ventricular surface where high Na CSF acts to cause natriuresis and increased ADH secretion is within the V3V region but not in the AV3V.

Animals↗
PubMed1993

Bumetanide decreases canine cerebrospinal fluid production. In vivo evidence for NaCl cotransport in the central nervous system.

Na/K/2Cl cotransport carrier plays an important role in fluid absorption and secretion in many epithelial tissues. The role of the carrier, however, in mammalian choroidal cerebrospinal fluid (CSF) production has been controversial. We used ventriculo-cisternal perfusion (VCP) labeled with blue dextran with or without bumetanide and measured choroidal CSF production in anesthetized, and paralyzed, mechanically ventilated dogs. During 3 h of VCP, mean intracerebroventricular and arterial pressures, PaCO2, pH, [HCO3-], and serum osmolality remained normal in both groups (n = 9 in each group). Beginning 90 min after the start of VCP, choroidal CSF production was measured every 15 min. In group I (control group), values for CSF production (means +/- SD) were 49 +/- 20, 49 +/- 21, 51 +/- 21, 51 +/- 23, 48 +/- 20, 56 +/- 24, and 48 +/- 20 microliters/min, at 90, 105, 120, 135, 150, 165, and 180 min, respectively. These values did not differ significantly from each other. In group II (bumetanide group), after baseline control CSF production had been determined at 90 and 105 min, bumetanide (10(-4) mol/liter) was added to VCP. Mean values for CSF production were 54 +/- 15 and 52 +/- 17 microliters/min before, and 39 +/- 25, 34 +/- 19, 28 +/- 10, 30 +/- 17, and 30 +/- 18 microliters/min after addition of bumetanide at 90, 105, 120, 135, 150, 165, and 180 min, respectively. Comparing the two groups, baseline values for CSF production measured at 90 and 105 min did not differ significantly. After addition of bumetanide (group II), however, decrements in CSF production varied from 30 +/- 27% at 120 min to 47 +/- 14% at 150 min, which were significantly different from changes in group I. The results of this study indicate that NaCl cotransport carrier is involved in secretion of CSF in dogs, and inhibition of the transporter results in approximately 50% reduction in CSF production.

Animals↗
PubMed2005

Vaccinia virus complement control protein diminishes formation of atherosclerotic lesions: complement is centrally involved in atherosclerotic disease.

Complement is known to be activated in atherosclerotic lesions, but the importance of this event in disease pathology is a matter of debate. Studies of rabbits fed a high-fat diet have indicated complement activation as a rate-limiting step, whereas results from genetically modified mouse strains (ApoE-/- or LDLR-/-) have failed to support this finding. To resolve whether this reflects differences between species or between genetically driven and diet-induced disease, we studied the effect of a complement inhibitor, vaccinia virus complement control protein (VCP), on C57BL/6 mice, the background strain of ApoE-/- and LDLR-/- mice. Atherosclerosis was induced by a high-fat diet, and VCP (20 mg/kg) was injected once per week after the eighth week. Fatty streak development was monitored at 15 weeks by microscopic examination of oil red-O-stained sections from the root of the aorta. VCP injections led to significant (50%) reduction of lesion size (P = 0.004). Lesions were marked by gradual accumulation of lipids and macrophages but did not develop beyond the fatty streak stage. VCP activity disappeared from serum in 4 days, and the possibility therefore exists that a higher level of protection may be achieved by more frequent injections. We conclude that the development of fatty streaks in diet-induced atherosclerotic disease can be significantly retarded by prophylactic treatment with a complement inhibitor. These results support previous findings from complement-deficient rabbits and suggest that the pathogenesis of atherosclerosis in diet-induced disease differs from that induced by major defects in lipid metabolism.

Animals↗
PubMed2004

Molecular mechanisms, emerging etiological insights and models to test potential therapeutic interventions in Alzheimer's disease.

Alzheimer's disease (AD) is a common cause of dementia, resulting from accumulated beta-amyloid protein deposits in the brain. As the population ages the incidence of AD is also on the rise. The incidence is very high in the developed countries where life expectancy is high, but it is also rising rapidly in the developing countries. Caring for patients suffering from AD is a major economic burden. The mechanisms underlying the neuropathology of AD are slowly being unravelled. Here we explore the many models and theories, which have been proposed over the years. We then discuss a potential therapeutic agent, vaccinia virus complement control protein (VCP), involved in modulating the complement system in AD. VCP has been shown in in vitro studies to block the complement activation caused by the beta peptide. Traumatic injuries to the brain are well known risk factors associated with the development of AD. VCP can also enhance functional recovery resulting from traumatic brain injury and may be able to slow the progression of traumatic brain injury to AD. Here we describe strategies for testing this hypothesis and evaluating other agents such as VCP.

Alzheimer Disease↗
PubMed2002

[A challenge for revealing common molecular mechanisms underlying neurodegenerative disorders].

Many neuodegenerative disorders manifest disease-specific phenotypes, and thus it was thought impossible to deduce a common molecular mechanism underlying many, if not all, neurodegenerative disorders. However, protein aggregates and vacuoles are almost universally found in degenerating neurons, suggesting the existence of similar molecular processes in neuronal cell death. In 1994, we identified the gene responsible for Machado-Joseph disease (MJD). Not only MJD but also another 8 inherited neurodegenerative diseases, including Huntington's disease are caused by the expansion of CAG repeats encoding polyglutamines. Indeed, we have shown that polyglutamines have the ability to self-aggregate and induce neurodegeneration and neuronal cell death, leading to a proposal of 'polyglutamine disease'. Furthermore, we have identified ter94/VCP, a member of the AAAAT-Pase, as a key molecule in neurodegeneration. VCP co-localizes not only with polyglutamine aggregates but also other protein aggregates and Lewy bodies. Moreover, profound deficits in its ATPase activity are found to severely affect ER quality control, leading to abnormal ER expansion and cell death. These lines of evidence indicate that VCP functions not only as a common sensor for abnormal protein accumulations but also as a mediator of neurodegenerative phenotypes; excessive accumulation of abnormal proteins may inactivate VCP's ATPase in several neurodegenerative disorders, eventually leading to the neurodegenerations. A proper regulation of VCP function is thus proposed to lead to novel treatments that are effective in a broad spectrum of neurodegenerative diseases.

Adenosine Triphosphatases↗
PubMed2002

[The prognostic role of electromyography in vocal cord paralysis].

OBJECTIVE: To predict the recovery of vocal cord paralysis (VCP) by using electromyography (EMG). METHOD: The characteristics of EMG of 46 patients with unilateral VCP were assessed to determine the most useful factors in determining prognosis. The factors include the duration, amplitude, waveform morphology, root-mean-square, and time interval. RESULT: A positive prognosis for laryngeal recovery was indicated when the following EMG features were present in the immobile vocal fold during voluntary tasks if EMG was performed during 6 months of the onset of VCP: normal motor unit waveform morphology; no electrical silence. This predictive rate is 76%. When the root-mean-square value is greater than 26 microV, the predictive rate is 80%. On the basis of the criteria, all the prognostic rate is 84%. CONCLUSION: The results support the concept that EMG record is valuable in determining prognosis performed during 6 months of the onset of VCP.

Adult↗
PubMed2005

[Expression and clinical significance of p185 and CD44v6 in laryngeal squamous cell carcinoma].

OBJECTIVE: To investigate the expression and the clinical significance of proto-oncogene cerbB-2 proteins p185 and adhesion molecules CD44v6 in laryngeal squamous cell carcinomas (LSCC) and the relationship between them. METHOD: expression of p185 and CD44v6 was studied by immunohistochemical analysis from 63 cases of LSCC, 20 cases of adjacent safety margin (ASM) and 18 cases of vocal cord polyp(VCP). RESULT: There were no expression of p185in VCP, Significant differences (P < 0.05) were observed between the two group; there was significant differences among the different pathologic degree I, II, III; The expression of p185 was not related to age and clinical stage. Significant differences (P < 0.05) were found among LSCC, VCP and ASM; there was no differences between the different pathologic degree I, II, III. The expression of CD44v6 was not related to age and clinical stage. Significant correlation was observed between the expression of p185 and CD44v6 in LSCC. CONCLUSION: p185 probably plays an important role during the carcinogenesis and progression process of LSCC. While CD44v6 has the important function only in the carcinogenesis process of LSCC. The expression of p185 and CD44v6 were higher in ASM than in VCP. It indicates that p185 and CD44v6 were probably the unstable factor in ASM which related to the recurrent of laryngeal carcinoma, and they may cooperate with each other.

Adult↗
PubMed2006

Deiminated Epstein-Barr virus nuclear antigen 1 is a target of anti-citrullinated protein antibodies in rheumatoid arthritis.

OBJECTIVE: To test the hypothesis that deimination of viral sequences containing Arg-Gly repeats could generate epitopes recognized by anti-citrullinated protein antibodies (ACPAs) that are present in rheumatoid arthritis (RA) sera. METHODS: Multiple antigen peptides derived from Epstein-Barr virus (EBV)-encoded Epstein-Barr nuclear antigen 1 (EBNA-1) were synthesized, substituting the arginines with citrulline, and were used to screen RA sera. Anti-cyclic citrullinated peptide antibodies were purified by affinity chromatography and tested on a panel of in vitro deiminated proteins. Their ability to bind in vivo deiminated proteins was evaluated by immunoprecipitation, using EBV-infected cell lines. RESULTS: Antibodies specific for a peptide corresponding to the EBNA-1(35-58) sequence containing citrulline in place of arginine (viral citrullinated peptide [VCP]) were detected in 50% of RA sera and in <5% of normal and disease control sera. In addition, affinity-purified anti-VCP antibodies from RA sera reacted with filaggrin-derived citrullinated peptides, with deiminated fibrinogen, and with deiminated recombinant EBNA-1. Moreover, anti-VCP antibodies immunoprecipitated, from the lysate of calcium ionophore-stimulated lymphoblastoid cell lines, an 80-kd band that was reactive with a monoclonal anti-EBNA-1 antibody and with anti-modified citrulline antibodies. CONCLUSION: These data indicate that ACPAs react with a viral deiminated protein and suggest that EBV infection may play a role in the induction of these RA-specific antibodies.

Adult↗
PubMed2002

Yeast two-hybrid screening identifies binding partners of human Tom34 that have ATPase activity and form a complex with Tom34 in the cytosol.

In the accompany paper (Mukhopadhyay, A., Avramova, L. V. and Weiner, H., Arch. Biochem. Biophys.), it was shown that Tom34, a previously proposed putative translocase of the mitochondrial outer membrane, binds to the mature region of a precursor protein and appears to be a cytosol protein. Here Tom34 was used as bait in a yeast two-hybrid screening to search for its potential binding partners. Two of the identified proteins were the ATPase-related valosin-containing protein (VCP) and the lysosomal H(+)-transporting ATPase member M (ATP6M). Tom34 was found primarily in the cytosol while VCP and ATP6M were found in the cytosol as well as in nonmitochondrial organelles. Tom34 formed a approximately 400-kDa complex with them in the cytosol. Tom34 was found to possess a weak ATPase activity that did not change when associated with VCP. The tetratricopeptide repeat (TPR) motif region of Tom34 (residue 201-256) was responsible for binding to the other proteins. Tom34 appears not to be a member of the mitochondrial outer membrane translocase family but might function as a chaperone-like protein during protein translocation.

Adenosine Triphosphatases↗
PubMed1995

Severe and prolonged inflammatory response to localized cowpox virus infection in footpads of C5-deficient mice: investigation of the role of host complement in poxvirus pathogenesis.

Poxviruses are a large, complex group of highly successful pathogens that cause disease in humans and other animals. They encode several proteins postulated to be involved in the evasion of host immunity and therefore serve as excellent models for understanding virus-host interaction during the early stages of viral infection. Vaccinia virus, the best characterized member of the poxviridae family, encodes a 35-kDa major secretory polypeptide termed vaccinia virus complement control protein (VCP), which is structurally related to the family of human and mouse complement control proteins. Members of the family of complement control proteins have been shown to inhibit complement-mediated opsonization of bacteria and induction of inflammatory and phagocytic responses in vitro. Insertional inactivation of the VCP gene results in attenuation of viral virulence in vivo. The role of host complement in the inflammatory response to poxvirus infection has not been systematically investigated. Prior to determining the role of VCP on inflammatory responses in vivo, we decided to investigate the role of host complement in the progression of viral infection. We have compared the effects of injection of cowpox virus, primarily a rodent virus, into footpads of congenic mice strains B10.D2/nSnJ (C5-sufficient) and B10.D2/oSnJ (C5-deficient). The effects of the injection were monitored macroscopically by measuring the specific swelling response immediately following primary injection and subsequently after reinfection and by histological examination of the stained sections of the footpads. Our results indicate that there is a significant variation in the primary response in the two different mouse strains to cowpox virus infection. The specific swelling response observed in measurements from the footpads of the B10.D2/oSnJ mice was significantly greater, persisted for a longer duration, and was accompanied by severe ulceration, edema, induration, and hemorrhaging. Reinjection of the footpads after a 3-month period, during which time the swelling had subsided and the footpad had fully recovered to its original size and appearance, showed no significant differences between the two strains. This strongly suggests that the host complement plays a significant role during the initial response to poxvirus infection.

Animals↗
PubMed1987

Treatment of adult acute lymphoblastic leukemia. Preliminary results of a trial from the French Group.

We present here the results of a cooperative trial in 244 adult patients with acute lymphoblastic leukemia. Induction therapy with vincristine, cytoxan, and prednisone (VCP) gave the same complete remission rate after one course as more aggressive induction with vincristine, rubidazone, araC, and prednisone (VRAP) due to increased toxic death in the aggressive arm. Because of high efficacy of salvage therapy with VRAP regimen in patients failing to achieve CR with VCP regimen, patients initially randomized to receive VCP had a significantly higher CR rate than patients initially receiving VRAP (87% vs. 73%, p = 0.01). Patients randomized to receive postremission consolidation using adriamycin, araC, and asparaginase (AAA) prior to maintenance had a significantly longer remission than patients not receiving consolidation (p less than 0.005). At the time of analysis allogeneic bone marrow transplantation does not significantly increase disease-free survival when compared with intensive consolidation chemotherapy.

Adult↗