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PubMed2004

Selective activation of ceruloplasmin promoter in ovarian tumors: potential use for gene therapy.

Gene therapy provides a novel treatment approach to cancer patients. Ideally, expression of therapeutic genes driven by cancer-specific promoters would only target tumors resulting in minimal toxicity to normal tissues. While there is a need of more effective and tolerable treatments for ovarian cancer patients, we aimed to identify gene promoters with high activity in ovarian tumors that can be potentially used in gene therapy to drive the expression of a therapeutic gene in tumors. To identify such promoters, a literature search was performed to reveal genes that are preferentially expressed in ovarian cancer compared with normal ovarian tissue. We found that the ceruloplasmin promoter drove up to 30-fold higher luciferase expression in ovarian cancer cells compared with immortalized normal cells. Furthermore, deletion studies revealed an activator protein-1 (AP-1) site in the ceruloplasmin promoter to be critical for optimal ceruloplasmin promoter activity. Ceruloplasmin promoter activity was significantly activated by 1-O-tetradecanoyl phorbol-13-acetate, a c-jun activator, and conversely suppressed by SP600125, a c-jun inhibitor. Consistently, the ceruloplasmin AP-1 site was specifically recognized by c-jun both in vitro and in vivo. Immunohistochemical analyses of human ovarian cancer specimens showed a direct correlation (r = 0.7, P = 0.007) between expression levels of c-jun and ceruloplasmin. In nude mice carrying SKOV3.ip1 xenografts, the ceruloplasmin promoter demonstrated significantly higher activities in tumors compared with normal organs. Together, these results suggest that the ceruloplasmin promoter activity is significantly enhanced in ovarian cancer and therefore may be exploited as a promising cancer-specific promoter in developing new gene therapy strategies for ovarian cancer.

Cell Line, Tumor↗
PubMedDate not supplied

Copper, ceruloplasmin and superoxide dismutase in patients with Alzheimer's disease . a case-control study.

The copper-containing enzyme superoxide dismutase (SOD) is a key enzyme in suppressing the amounts of superoxide anion radicals. Ceruloplasmin, the copper-transporting protein in plasma, also possesses an important redox capacity. In this study the levels of copper and ceruloplasmin as well as SOD-activity and ceruloplasmin oxidative activity were analyzed in order to throw some light on possible defects in copper mechanisms in patients diagnosed with Alzheimer's disease (AD). The study included 44 patients with AD and their healthy age- and gender-matched controls. No difference of significance was seen when comparing the copper or ceruloplasmin concentration in plasma of AD patients to that of their paired controls. The SOD activity in red blood cells was significantly lower in the patients than in their controls (p = 0.019). The ceruloplasmin oxidative activity in plasma of Alzheimer's patients was greatly reduced as compared to that of age- and gender-matched controls and the difference was highly significant (p = 0.0005). Ceruloplasmin activity and SOD activity were not found to be intrinsically correlated. It was postulated that reduced oxidative activity of ceruloplasmin in plasma might be either a cause or a consequence of AD and that reduced SOD activity might further add to the oxidative disturbances in AD due to defective ceruloplasmin activity.

Aged↗
PubMed1995

Urinary excretion rate of ceruloplasmin in non-insulin-dependent diabetic patients with different stages of nephropathy.

The level of ceruloplasmin, which is a more negatively charged protein than albumin, was measured by an immunoradiometric assay in timed overnight urine and serum samples from patients with non-insulin-dependent diabetes mellitus and healthy controls. None of the plasma proteins examined showed any cross-reactivity in this assay. A linear correlation was seen between the ceruloplasmin level and the serial dilution of the sample. Western blot analysis using concentrated urine samples showed that the molecular weight of ceruloplasmin in the urine sample was the same as that of ceruloplasmin in the serum and standard samples. These findings indicated that the substance detected by this assay was truly ceruloplasmin. The urinary ceruloplasmin excretion rate (CER) and clearance of ceruloplasmin increased in parallel with the progression of albuminuria. The highest CER was found in macroalbuminuric patients, followed by micro- and normoalbuminuric patients and the healthy control subjects, the differences between the groups being significant. In view of the fact that the isoelectric point of ceruloplasmin (4.4) is more acidic than that of albumin, the present findings suggested that an enhanced CER was due either to the alteration of charge selectivity in the glomerular basement membrane with unaltered tubular function or to a defect of the non-discriminatory pores (shunt pathway) with unaltered tubular function.

Adult↗
PubMed1992

A prognostic role for ceruloplasmin in the diagnosis of indolent and recurrent inflammation.

Ceruloplasmin is increased in infections, inflammatory diseases, and neoplastic diseases and may be scarcely visible to the naked eye because it imparts a faint green color to the serum. This poses an interesting question as to a possible prognostic role for ceruloplasmin in the diagnosis of persistent or recurrent infection. The clinical course of 50 patients with tainted serum was reviewed retrospectively and ceruloplasmin levels correlated with diagnosis and outcome. Group I consisted of 20 healthy controls with normal ceruloplasmin levels: 35.1 +/- 2.0 mg/dL (range 25 to 45 mg/dL). Group II was made up of 23 surgical patients; 10 of these patients had elevated levels of ceruloplasmin, nine of whom had significant infections (64.2 +/- 3.2 mg/dL), and one patient was on estrogen (73.7 mg/dL). Group III consisted of 27 medical patients; 25 of these patients had elevated levels of ceruloplasmin, 20 of whom had infections (54.1 +/- 2.6 mg/dL), and five had malignancies (61.0 +/- 3.0 mg/dL). Ceruloplasmin levels were consistently elevated in all patients with infections relative to controls (P less than .001) with a variable response in other disease states. Therefore, ceruloplasmin may be useful as a serum marker for indolent or recurrent infections.

Biomarkers↗
PubMed2004

Effect of estrogen on plasma ceruloplasmin level in rats exposed to acute stress.

BACKGROUND: Plasma ceruloplasmin, a copper containing protein, belongs to a class called acute phase proteins. Reduced level of ceruloplasmin was associated with Wilson's disease and Menke's kinky hair disease in man, primarily affecting copper metabolism. Stress was known to increase Ceruloplasmin. Several stress associated changes were commonly observed in women at menopause and also those who underwent overiectomy. Present experiment investigated the effect of estrogen on ceruloplasmin level in acute stress. AIMS: To assess the estradiol induced changes in plasma ceruloplasmin concentration on exposure of the rats to acute stress. SETTINGS AND DESIGN: Acute stress was induced by forcing the rats to swim till exhaustion. The rats were overiectomised bilaterally to remove the primary source of sex hormones. And hormone replacement was done later. MATERIAL AND METHODS: Wistar albino female rats were used. Acute stress was induced before overiectomy, following recovery from surgery, and again after Estradiol Valerate injection (for 10 days) in same group of rats. The plasma ceruloplasmin was estimated immediately after stress during each stage--that is preoperative control, stressed control, after overiectomy and then following treatment with Estradiol Valerate. STATISTICAL ANALYSIS USED: Paired sample T test was applied to analyze the findings. RESULTS: We found lowest ceruloplasmin level after stress in overiectomised animals, while on substitution of estradiol the trend appeared to be reversed. CONCLUSION: The result suggested a direct effect of estrogen on hepatic ceruloplasmin production/release and this could account for some of the beneficial effects of hormone replacement therapy.

Acute Disease↗
PubMed1988

Chicken ceruloplasmin. Evidence in support of a trinuclear cluster involving type 2 and 3 copper centers.

Ceruloplasmin was isolated to purity from chicken plasma by a single-step chromatography on amino-ethyl-derivatized Sepharose. Molecular mass, as estimated by nonreducing sodium dodecyl sulfate-electrophoresis, was approximately 140 kDa, slightly higher than that found for ceruloplasmins from other sources. Specific activity as p-phenylenediamine oxidase was five times higher than that reported for mammalian ceruloplasmins. The copper content was estimated to be 5.01 +/- 0.35 atoms per protein molecule, 50% of which was EPR-detectable. The EPR spectrum was completely devoid of any signal typical of the type 2 copper as seen in the other blue multicopper oxidases and in ceruloplasmin from mammalian species. Anaerobic reduction of chicken ceruloplasmin resulted in the disappearance of the 330 nm optical band typical of type 3 copper, which was followed by the appearance of an EPR signal typical of type 2 copper. Subsequently, the type 1 copper and finally the newly formed type 2 copper were reduced. The original optical and EPR spectra were recovered within few minutes upon exposure of reduced ceruloplasmin to air. It is concluded that in oxidized chicken ceruloplasmin type 2 copper interacts with the diamagnetic pair responsible for the 330 nm absorption in such a way as to become EPR-undetectable and that the interaction is relieved by reduction of the pair. Whether this interaction is intrinsically weaker in other blue oxidases and ceruloplasmins studied or is lost with standard preparation procedures remains to be established.

Animals↗
PubMed1989

Copper transport: insights into a ceruloplasmin-based delivery system.

Ceruloplasmin binds to the membranes of K562 cells. The binding has been shown to result in a temperature-dependent transfer of ceruloplasmin-bound copper into the cytosol. Ascorbic acid (100 microM) stimulates the transmembrane transfer nearly 10-fold, depending on the initial concentration of 67Cu-ceruloplasmin. The protein moiety of ceruloplasmin does not enter the cells. Bathocuproine disulfonate, a chelator specific for cuprous copper, inhibits the uptake, suggesting copper atoms are reduced concomitant with their removal from ceruloplasmin. Cytosolic 67Cu from ceruloplasmin was found mainly bound to Cu, Zn superoxide dismutase, the major cytosolic copper protein in these cells. Evidence supporting the various phases in the ceruloplasmin-mediated transport mechanism are presented.

Ascorbic Acid↗
PubMed1977

Determination of histaminase (diamine oxidase) activity by o-dianisidine test: interference of ceruloplasmin.

Until now o-dianisidine was used as an indicator substance in a test system for the determination of diamine oxidase. More recently, however, this substance was also used to measure ceruloplasmin activity. A study of the test principles revealed that o-dianisidine was the one denominator for both enzymes. As it was found for diamine oxidase the indicator was oxidized via peroxidase mediated H2O2 cleavage. Ceruloplasmin, however, oxidized o-dianisidine directly with resulting free radical formation. An addition of histamine dihydrochloride or putrescine dihydrochloride to an incubation mixture, containing ceruloplasmin as enzyme and o-dianisidine or p-phenylene-diamine as substrates, produced an activation of the enzyme, being more than 10-fold in the presence of 1 X 10(-2) M putrescine at pH 7.0. It was assumed that an allosteric effect of the dihydrochloride component might be responsible for this activation. When the activity of purified diamine oxidase was determined by the o-dianisidine test and by the isotope assay, a very good correlation between both methods was found. But, in a mixture of diamine oxidase and ceruloplasmin, no differentiation between the two enzymic activities by the o-dianisidine test was possible. This observation demonstrated an interference of ceruloplasmin when the o-dianisidine method was used for the determination of diamine oxidase activity. To apply our findings also in vivo the amine oxidase activity increasing in guinea-pig plasma during inflammation, was determined by the o-dianisidine test and by specific methods for some amine oxidase. Despite an enhanced oxidation of the o-dianisidine observed, only an increase of ceruloplasmin activity was found. It was concluded that ceruloplasmin had no 'histaminase activity' as has been assumed by other authors using the o-dianisidine test.

Amine Oxidase (Copper-Containing)↗
PubMed1985

Purification and partial characterization of ceruloplasmin from chicken serum.

The preparation and properties of ceruloplasmin from chicken serum are described. Ethanol-CHCl3 was used to precipitate the crude protein, followed by adsorption and elution from DEAE-Sephadex. Further treatment with Sephadex G-200 and CM-Sephadex yielded an intensely blue protein judged 1572-fold purer than starting serum. epsilon-Aminocaproic acid (0.02 M) was present in all buffers and starting sera. Chicken ceruloplasmin appears to be a single polypeptide, apparent Mr 124,000, with an A610/A280 ratio of 0.07 and an absorption maximum at 602 nm. Hexose, hexosamine, and sialic acid accounted for 7.2% of the weight; copper represented 0.20%, which suggested four or five copper atoms per molecule. Chicken ceruloplasmin catalyzed the azide-sensitive oxidation of p-phenylenediamine (PPD) and N,N'-dimethyl-p-phenylenediamine (DPD), and showed ferroxidase activity similar to that of human ceruloplasmin. Its amino acid composition, although similar in many residues to human ceruloplasmin, was decidedly lower in methionine and tyrosine. The chicken protein had one-third the sialic acid content of human ceruloplasmin and showed immunochemical nonidentity with human ceruloplasmin.

Amino Acids↗
PubMed1987

Ceruloplasmin gene expression in human cancer cells.

The copper transport protein, ceruloplasmin, is suggested to have a role in cancer since it is involved in angiogenesis and neovascularization. In order to understand the role of ceruloplasmin in malignant cells, we have recently isolated and sequenced a human ceruloplasmin cDNA clone. In the present study, we have investigated the ceruloplasmin gene expression in human colon and breast cancer cell lines. The poly (A) RNA from human colon (WiDr) and human breast (MCF-7) cancer cell lines was analyzed for the presence of ceruloplasmin mRNA. The Northern blot analysis revealed the presence of a 3.7 kb band of ceruloplasmin mRNA in these cell lines. Dot blot analysis revealed that ceruloplasmin mRNA is at least three fold more abundant in tumor cells as compared to normal rat liver.

Breast Neoplasms↗
PubMed2005

Ceruloplasmin in neurodegenerative diseases.

For decades, abnormalities in ceruloplasmin (Cp) synthesis have been associated with neurodegenerative disease. From the early observation that low circulating serum ceruloplasmin levels served as a marker for Wilson's disease to the recent characterization of a neurodegenerative disorder associated with a complete lack of serum ceruloplasmin, the link between Cp and neuropathology has strengthened. The mechanisms associated with these different central nervous system abnormalities are very distinct. In Wilson's disease, a defect in the P-type ATPase results in abnormal hepatic copper accumulation that eventually leaks into the circulation and is abnormally deposited in the brain. In this case, copper deposition results in the neurodegenerative phenotype observed. Patients with autosomal recessive condition, aceruloplasminemia, lack the ferroxidase activity inherent to the multi-copper oxidase ceruloplasmin and develop abnormal iron accumulation within the central nervous system. In the following review ceruloplasmin gene expression, structure and function will be presented and the role of ceruloplasmin in iron metabolism will be discussed. The molecular events underlying the different forms of neurodegeneration observed will be presented. Understanding the role of ceruloplasmin within the central nervous system is fundamental to further our understanding of the pathology observed. Is the ferroxidase function more essential than the antioxidant role? Does Cp help maintain nitrosothiol stores or does it oxidize critical brain substrates? The answers to these questions hold the promise for the treatment of devastating neurodegenerative conditions such as Alzheimer's and Parkinson's diseases. It is essential to further elucidate the mechanism of the neuronal injury associated with these disorders.

Animals↗
PubMed2006

Retrospective determination of ceruloplasmin in newborn screening blood spots of patients with Wilson disease.

Wilson disease is an autosomal recessive disorder of copper transport, caused by the reduced or absent function of the Wilson disease gene ATP7B on chromosome 13. The disease is characterized by reduced incorporation of copper into the ceruloplasmin protein and reduced excretion of copper into the bile. Wilson disease is effectively treated if detected early. Our study goals were to determine the feasibility of a population screening for Wilson disease using dried blood spots and to characterize the base-line ceruloplasmin concentration in newborn blood spots of patients with Wilson disease. Ceruloplasmin was analyzed in dried blood spots obtained from 353 Mayo Clinic pediatric volunteers aged from 3 months to 18 years and from 1045 anonymous newborn screening specimens using a sandwich enzyme-linked immunosorbent assay. The original newborn screening blood spots were retrieved from two patients with Wilson disease along with age-matched controls for ceruloplasmin determination. The mean (+/-SD) concentration of ceruloplasmin in the pediatric blood spots was 40.0+/-14.4 mg/dL (range 13.1 to >60 mg/dL) and newborn blood spots was 47.2+/-15.5mg/dL (range 6.5 to >60 mg/dL). Ceruloplasmin in the newborn blood spots from two Wilson disease patients were 2.6 and 2.8 mg/dL, respectively. The newborns affected with Wilson disease had significantly lower ceruloplasmin levels in blood spots than unaffected newborns. These findings support that presymptomatic screening for Wilson disease using dried blood spots could be possible, even in the newborn period.

Adenosine Triphosphatases↗
PubMed2002

Ceruloplasmin carries the anionic glycan oligo/poly alpha2,8 deaminoneuraminic acid.

Oligo/poly alpha2,8 deaminoneuraminic acid (KDN), a unique posttranslational protein modification, was found on megalin and a not yet characterized 150 kDa glycoprotein. We purified this glycoprotein from rat testis and identified it as ceruloplasmin. Furthermore, immunoprecipitated ceruloplasmin from rat thymus, ovary, blood serum, and postnatal day 2 but not adult lung and brain was immunoreactive for oligo/poly alpha2,8 KDN. The immunoreactivity for oligo/poly alpha2,8 KDN on purified serum ceruloplasmin was abolished by N-glycosidase F treatment but not by beta-elimination, indicating that it is present on N-glycosidically linked oligosaccharides. However, the copper binding activity of ceruloplasmin was independent of the presence of the anionic glycan. By immunohistochemistry, ceruloplasmin was detectable in histologically defined regions in rat ovary, thymus, and spleen. Likewise, by RT-PCR, ceruloplasmin expression was found in various non-hepatic rat tissues and showed a developmentally regulated pattern. Thus, ceruloplasmin, in addition to megalin, represents a glycoprotein carrying oligo/poly alpha2,8 KDN.

Amidohydrolases↗
PubMed1991

Ceruloplasmin stimulates thymidine incorporation by CCL-39 cells in the absence of serum or growth factors.

The incorporation of tritiated thymidine into CCL-39 cells grown in the absence of fetal calf serum or other growth factors is greatly increased by low concentrations of ceruloplasmin. The stimulation is greater than observed with serum or thrombin. Addition of serum decreases the thymidine incorporation with ceruloplasmin to the level with serum alone. As with serum, the response to ceruloplasmin is high at both 20% and 1% oxygen, which is consistent with the action of ceruloplasmin as an oxidant with a high affinity for oxygen. Since transplasma membrane electron transport increases cell growth and thymidine incorporation, ceruloplasmin may act as a terminal oxidase for ferrous iron or ascorbate to stimulate transplasma membrane electron transport. The four electron transfer from ceruloplasmin to oxygen to form water will prevent peroxide formation at the cell surface. Alternatively, superoxide formation inside the cell or membrane could employ the superoxide dismutase function of ceruloplasmin to produce peroxide. Either mechanism would be consistent with the previously described stimulation of growth by external oxidants.

3T3 Cells↗
PubMed2001

Assessment of copper status in pregnancy by means of determining the specific oxidase activity of ceruloplasmin.

BACKGROUND: Conditions not directly related to copper nutriture, such as pregnancy, infections and inflammation, which increase serum copper concentration even during copper deprivation, may be expected to conceal changes in copper status. It has been suggested that the specific enzymatic activity of ceruloplasmin (activity per unit mass of enzyme protein) may be a sensitive indicator of copper status and is not affected by factors such as hormones or sex. In this study, we investigated the behaviour of specific oxidase activity of ceruloplasmin and the copper/ceruloplasmin ratio in pregnant women. METHODS: Copper, immunoreactive ceruloplasmin and its oxidase activity were determined in serum from 52 women in the last trimester of normal pregnancy, and in 50 control women of similar age living in the same area and who were not taking oral contraceptives. The results are expressed as mean+/-S.E.M. RESULTS: In the group of pregnant women, significantly higher serum levels of copper, ceruloplasmin and its oxidase activity were found than in the control group (p < 0.001). In both groups, a high correlation was found between these biochemical variables (r > or =0.905, p < 0.001). However, in the group of pregnant women the specific oxidase activity for ceruloplasmin (364.4+/-3.3 vs. 407.5+/-3.8 U/g) and the copper/ceruloplasmin ratio (2.82+/-0.03 vs. 3.19+/-0.04 microg/mg) were significantly lower than in the control group (p < 0.001). CONCLUSIONS: Although pregnancy accelerates the rate of ceruloplasmin protein synthesis and release with an increase of serum copper, the decrease in specific oxidase activity of circulating ceruloplasmin would be an indicator of the degree of depletion of the mother's copper deposits in order to deal with the foetus' needs.

Adolescent↗
PubMed1998

Requirement of intact human ceruloplasmin for the glutathione-linked peroxidase activity.

Structural integrity may be needed for the glutathione-linked peroxidase activity of human ceruloplasmin. Intact human ceruloplasmin has a potent peroxidase property to decompose H2O2 in the presence of reduced glutathione. However, the fragment of approximately 116000 Da produced by proteolytic degradation had less than one-third of the glutathione-linked peroxidase activity of intact ceruloplasmin. When further proteolysis occurred, glutathione-linked peroxidase activity of human ceruloplasmin disappeared. In contrast, ceruloplasmin (116000 Da and <96000 Da) fragmented by proteolysis significantly removed H2O2 irrespective of the presence of reduced glutathione. Although proteolytic fragmentation of ceruloplasmin occurs, the antioxidant activity of ceruloplasmin that prevents DNA strand breaks in a metal-catalyzed reaction system was significantly maintained.

Antioxidants↗
PubMed1982

Comparison of the catalytic oxidation of cysteine and o-dianisidine by cupric ion and ceruloplasmin.

Several features of the catalytic oxidation of cysteine by ceruloplasmin and nonenzymic Cu(II) at pH 7 have been compared. The oxidation of cysteine by ceruloplasmin has several properties in common with the Cu(II) catalyzed oxidation of cysteine: pH maxima, thiol specificity, lack of inhibition by anions, and high sensitivity to inhibition by copper complexing reagents. These two catalysts differed in their molecular activity, in their ability to oxidize penicillamine and thioglycolate, and in that H2O2 was produced as a primary product only during Cu(II) oxidation. The oxidation of cysteine by ceruloplasmin was compared also with the ceruloplasmin catalyzed oxidation of o-dianisidine, a classical pH 5.5 substrate. The mechanism of the oxidation of cysteine by ceruloplasmin at pH 7 differed from that of o-dianisidine oxidation because the latter substrate was inhibited by anions but not by copper complexing agents. Spectral and other data suggest that during the ceruloplasmin reaction with cysteine there is a one electron transfer from cysteine to ceruloplasmin resulting in the specific reduction of type 1b Cu(II).

Animals↗
PubMed2000

Immunochemical and enzymatic study of ceruloplasmin in rheumatoid arthritis.

Forty adult patients (30 women and 10 men) with rheumatoid arthritis (RA), treated with nonsteroidal anti-inflammatory drugs, were studied. Serum levels of immunoreactive ceruloplasmin, oxidase activity of the ceruloplasmin and total copper, as well as the specific oxidase activity (enzyme activity per unit of mass) and the copper/immunoreactive ceruloplasmin relationship were significantly higher in the group of patients than in the healthy control group (p < 0.001). However, no significant difference was found for the concentration of non-ceruloplasmin copper between both groups. A statistically significant negative correlation was obtained for the concentration of serum thiobarbituric acid-reacting substances with the immunoreactive ceruloplasmin and its oxidase activity in the group of patients (p < 0.005). These results suggest that in RA increases of serum copper are produced at the expense of the fraction linked to the ceruloplasmin, diminishing the proportion of apoceruloplasmin and other forms poor in copper. Although the increase in the serum concentration of ceruloplasmin might offer an additional safeguard against oxidative stress. it does not appear to have a beneficial effect upon the activity of the illness as evaluated by means the biological inflammation markers C-reactive protein, erythrocyte sedimentation rate and sialic acid.

Adult↗