Disease relevance of Cp

• During the acute-phase reaction, genes encoding CP, SAA, AGP, and HP demonstrate unique extrahepatic tissue specific patterns of expression in kidney, spleen, thymus, heart, brain, lung, testis, and epididymis [1].
• Aceruloplasminemia is an autosomal recessive disorder caused by mutations in the ceruloplasmin (CP) gene, and is characterized by a unique combination of neurovisceral iron overload and iron deficiency anemia [2].
• Thus, Cp(-/-) have mild microcytic, hypochromic anemia consistent with normal red cell formation but defective iron availability [3].
• Cp(-/-) and Cp(+/+) mice subjected to phenylhydrazine-induced hemolytic anemia exhibited identical decreases in hematologic parameters, but Cp(-/-) mice showed diminished recovery after removal of the stress [3].
• Ceruloplasmin and regulation of transferrin iron during Neisseria meningitidis infection in mice [4].

Psychiatry related information on Cp

• Therefore, the antioxidant effects of ceruloplasmin could have important implications for various neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease in which iron deposition is known to occur [5].

High impact information on Cp

• We describe here a novel gene, Heph, encoding a transmembrane-bound ceruloplasmin homologue that is mutant in the sla mouse and highly expressed in intestine [6].
• Ceruloplasmin gene defect associated with epilepsy in EL mice [7].
• In the central nervous system, abundant ceruloplasmin gene expression was detected in specific populations of astrocytes within the retina and the brain as well as the epithelium of the choroid plexus [8].
• Analysis of primary cell cultures confirmed that astrocytes expressed ceruloplasmin mRNA and biosynthetic studies revealed synthesis and secretion of ceruloplasmin by these cells [8].
• In situ hybridization of systemic tissues revealed cell-specific ceruloplasmin gene expression in hepatocytes, the splenic reticuloendothelial system and the bronchiolar epithelium of the lung [8].

Chemical compound and disease context of Cp

• Compared to controls, plasma nitrite concentrations were substantially reduced in ceruloplasmin knockout mice, which were more susceptible to liver infarction after ischemia and reperfusion [9].

Biological context of Cp

• We recently mapped the major gene, El-1, to chromosome 9 near the predicted location for the ceruloplasmin (Cp) gene [10].
• The significant increase in silver grain count over chromosome 15 in rats after hybridization with both the Cp and Tf probes suggests the presence of a related pseudogene cluster on this particular chromosome and thus favours its partial homeology to chromosome 7 [11].
• Use of the rat Cp DNA probe does not indicate synteny of the Cp and Tf genes in man and suggests the existence of a related DNA sequence in 15q11-13 [11].
• The copper requirement of the multicopper ferroxidases hephaestin and ceruloplasmin likely explains this link between copper and iron homeostasis in mammals [12].
• Cp(-/-) mice have below normal hematocrit, red cell hemoglobin and volume, and serum iron [3].

Anatomical context of Cp

• The coordinated actions of GPI-Cp and IREG1 may be required for iron efflux from neural cells, and disruption of this balance could lead to iron accumulation in the central nervous system and neurodegeneration [13].
• We also show that GPI-Cp colocalizes on the astrocyte cell surface with the divalent metal transporter IREG1 and is physically associated with IREG1 [13].
• Ceruloplasmin and lactoferrin may cooperate in the defense of the mammary gland in the postlactation period [14].
• Hephaestin is a membrane-bound multicopper ferroxidase necessary for iron egress from intestinal enterocytes into the circulation [15].
• Here, we demonstrate that Hp has both amine oxidase and ferroxidase activity in cultured cells and primary intestinal enterocytes with the use of both gel and solution assays [16].

Associations of Cp with chemical compounds

• Ceruloplasmin (Cp) is a ferroxidase that converts highly toxic ferrous iron to its non-toxic ferric form [13].
• Ceruloplasmin is an abundant serum glycoprotein containing greater than 95% of the copper found in the plasma of vertebrate species [17].
• Immunocytofluorescence analysis demonstrated that digoxigenin-labeled CP bound to P19 neurons and the proportion of responding neurons decreased with aging [18].
• It also plays an important role in detoxifying potentially harmful free ferrous iron to the less soluble ferric iron by virtue of the ferroxidase activity of the H subunit [19].
• Ferritin stimulation of a monokine inhibitor of lipopolysaccharide-augmented myelopoiesis is ferroxidase dependent [20].

Regulatory relationships of Cp

• Using differential display reverse transcription-polymerase chain reaction (DDRT-PCR), seven upregulated genes including S100 calcium binding protein A9 (S100A9) mRNA and antigenic determinant for rec-A protein mRNA and five downregulated genes including caseinolytic protease X (ClpX) mRNA and ceruloplasmin (CP) mRNA by cisplatin were identified [21].

Other interactions of Cp

• Ceruloplasmin gene defect associated with epilepsy in EL mice [10].
• Antioxidant and antibacterial genes are upregulated in early involution of the mouse mammary gland: sharp increase of ceruloplasmin and lactoferrin in accumulating breast milk [14].
• Both Cp and Tf genes were found to be syntenic in rodents, occupying with high probability the regions 9D and 9F1-3 in mice and 7q11-13 and 7q31-34 in rats respectively [11].
• Cp mRNA was detected in the developing mouse brain, where its expression domain was closely adjacent to that of Shh [22].
• Subsequently, mutations in the ceruloplasmin gene have been determined to result in the excessive iron accumulation seen in the pancreas, retina, and brain [23].

Analytical, diagnostic and therapeutic context of Cp

• Quantitative evaluation of expression of iron-metabolism genes in ceruloplasmin-deficient mice [2].
• To elucidate the role of ceruloplasmin in iron homeostasis, we created an animal model of aceruloplasminemia by disrupting the murine ceruloplasmin (Cp) gene [24].
• Phlebotomy of wild-type mice caused a striking shift of Cp from the duodenal epithelium to the underlying lamina propria, suggesting a critical function of Cp in basolateral iron transport [25].
• The interaction of digoxigenin-labeled CP with neurons was half-maximal at 120 nM by enzyme-linked immunosorbent assay and displaced by unlabeled CP [18].
• The role of hypoxia-inducible factor-1 in the induction of Cp by insulin was shown by electrophoretic mobility shift assays and by the absence of insulin-stimulated Cp promoter activation in mouse Hepa c4 cells deficient in hypoxia-inducible factor-1 activity [26].

References