Disease relevance of Gc

• When maintained on vitamin D-deficient diets for a brief period, the DBP-/-, but not DBP+/+, mice developed secondary hyperparathyroidism and the accompanying bone changes associated with vitamin D deficiency [1].
• Osteopathy and resistance to vitamin D toxicity in mice null for vitamin D binding protein [1].
• After an overload of vitamin D, DBP-/- mice were unexpectedly less susceptible to hypercalcemia and its toxic effects [1].
• Specific forms of renal Fanconi syndrome are associated with endocytic pathway dysfunction with disruption of megalin-mediated uptake DBP/25-(OH)D3 complex, producing metabolic bone disease in affected individuals as a prominent clinical finding [2].
• Prognostic utility of serum alpha-N-acetylgalactosaminidase and immunosuppression resulted from deglycosylation of serum Gc protein in oral cancer patients [3].

Psychiatry related information on Gc

• Mice homozygous for a DBP-null allele display less locomotor activity and free-run with a shorter period than otherwise isogenic wild-type animals [4].

High impact information on Gc

• We show that 25-(OH) vitamin D3 in complex with its plasma carrier, the vitamin D-binding protein, is filtered through the glomerulus and reabsorbed in the proximal tubules by the endocytic receptor megalin [5].
• BACKGROUND: The vitamin D(3)-binding protein (Gc protein)-derived macrophage activating factor (GcMAF) activates tumoricidal macrophages against a variety of cancers indiscriminately [6].
• Peak steady-state mRNA levels of the vitamin D-dependent calbindin-D9K gene were induced by 1,25(OH)2D more rapidly in the DBP-/- mice [1].
• A line of mice deficient in vitamin D binding protein (DBP) was generated by targeted mutagenesis to establish a model for analysis of DBP's biological functions in vitamin D metabolism and action [1].
• Thus, the role of DBP is to maintain stable serum stores of vitamin D metabolites and modulate the rates of its bioavailability, activation, and end-organ responsiveness [1].

Chemical compound and disease context of Gc

• Phthalate esters with short alkyl chains, such as di-ethyl (DEP), di-n-propyl (DPP), and di-butyl phthalate (DBP), have adjuvant effects on an FITC-induced contact hypersensitivity mouse model [7].

Biological context of Gc

• The fourth gene, Gc, encoding vitamin D-binding protein or group-specific component, maps to the same chromosome as the other family members, but linkage has not been established [8].
• This report describes the genetic and physical mapping of Gc in mouse and establishes that, although Gc is genetically linked to the other genes, its physical distance from them extends beyond the resolution range of yeast artificial chromosome cloning and pulsed-field gel electrophoresis [8].
• Population gene frequencies for these proteins binding vitamin D were in the range of those reported for Gc, and individuals of known Gc phenotype were found to have the corresponding vitamin-D-binding phenotype [9].
• Vitamin D-binding protein (DBP) has been reported to contribute to innate immunity [10].
• Anti-megalin antibodies produced a similar reduction in DBP/25-(OH)D3 endocytosis [2].

Anatomical context of Gc

• Initial studies revealed a marked defect in the ability of these DBP(-/-) mice to recruit cells to the peritoneum after localized thioglycolate injection [10].
• To verify prior in vitro and cell-based observations supporting this role, we assessed the ability of a recently developed DBP-null mouse line to recruit neutrophils and macrophages to a site of chemical inflammation [10].
• The interrupted DBP allele had been generated by homologous recombination in 129X1/SvJ embryonic stem cells and these cells were subsequently used to generate a line of DBP(-/-) (null) mice [10].
• Analysis of intercellular signal transmission among nonadherent (B and T) cells revealed that lyso-PC-treated B cells modify Gc protein to yield a proactivating factor, which can be converted by T cells to the macrophage-activating factor [11].
• Identification of the serum factor required for in vitro activation of macrophages. Role of vitamin D3-binding protein (group specific component, Gc) in lysophospholipid activation of mouse peritoneal macrophages [12].

Associations of Gc with chemical compounds

• Three lines of evidence are reported: (1) Polyacrylamide gel electrophoresis and autoradiography of serum labeled with (14-C)vitamin D3 revealed patterns of radioactive bands identical to those expected of the two Gc alleles [9].
• Group-specific component (Gc) proteins bind vitamin D and 25-hydroxyvitamin D [9].
• This review describes these new pathways for uptake of 25-hydroxy-vitamin-D3 and the gonadal sex-steroids (17beta-estradiol and testosterone) bound to vitamin D-binding protein and sex hormone-binding globulin respectively [13].
• This rapid process of macrophage activation was found to require a serum factor, the vitamin D3 binding protein (the human protein is known as group-specific component; Gc) [11].
• Vitamin D3-binding protein (Gc protein), a serum glycoprotein, is the precursor for the macrophage activating factor [3].

Physical interactions of Gc

• Recent studies have shown that vitamin D-binding protein (DBP)/25-(OH)D3 complex is one of the megalin/cubilin ligands [2].
• The influence of age, sex and strain on the serum concentration of transcortin (corticosteroid-binding globulin) and vitamin D-binding protein (DBP) in mice was investigated [14].

Other interactions of Gc

• Linkage between vitamin D-binding protein and alpha-fetoprotein in the mouse [8].
• In a previous study, the s locus was included in the same linkage group as serum albumin (Alb) and vitamin-D binding protein (GC) which are mapped on chicken (Gallus gallus) chromosome 4 (GGA4) [15].
• Incubation of Gc protein with a mixture of beta-galactosidase and sialidase efficiently generated the macrophage-activating factor [11].
• The antibody was subtyped IgG2b kappa and had a kd of 3.0 x 10(-8) M for antigen Gc [16].
• Transcortin and vitamin D-binding protein levels in mouse serum [14].

Analytical, diagnostic and therapeutic context of Gc

• (2) Immunoelectrophoresis and autoradiography of labeled serum reacted against antiserum to human Gc revealed labeling by (14-C)vitamin D3 of Gc-antibody precipitation ares [9].
• Deglycosylated Gc protein cannot be converted to macrophage activating factor, leading to immunosuppression [3].
• Competition assays with vitamin D3 and Gc in enzyme-linked immunosorbent assay indicate that the epitope of hDBP-1 on the Gc molecule may be related to the vitamin-D3-binding site [17].
• CONCLUSION: The difference of isoelectric focusing mobility in Gc protein and GcMAF would be useful to develop a GcMAF detection method [18].
• Gc protein from human serum was purified by affinity chromatography with 25-hydroxyvitamin D3-sepharose [19].

References