Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027960 (mole)
 21,279 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sulfated tyrosine residues within recombinant human factor VIII were identified by [35S]sulfate biosynthetic labeling of Chinese hamster ovary cells which express human recombinant factor VIII. Alkaline hydrolysis of purified [35S]sulfate-labeled factor VIII showed that greater than 95% of the [35S]sulfate was incorporated into tyrosine. [3H]Tyrosine and [35S]sulfate double labeling was used to quantify the presence of 6 mol of tyrosine sulfate per mole of factor VIII. Amino acid sequence analysis of thrombin and tryptic peptides isolated from [35S]sulfate-labeled factor VIII demonstrated tyrosine sulfate at residue 346 in the factor VIII heavy chain and at residues 1664 and 1680 in the factor VIII light chain. In addition, the carboxyl-terminal half of the A2 domain contained three tyrosine sulfate residues, likely at positions 718, 719, and 723. Interestingly, all sites of tyrosine sulfation border thrombin cleavage sites. The functional importance of tyrosine sulfation was examined by treatment of cells expressing factor VIII with sodium chlorate, a potent inhibitor of tyrosine sulfation. Increasing concentrations of sodium chlorate inhibited sulfate incorporation into factor VIII without affecting its synthesis and/or secretion. However, factor VIII secreted in the presence of sodium chlorate exhibited a 5-fold reduction in procoagulant activity, although the protein was susceptible to thrombin cleavage. These results suggest that tyrosine sulfation is required for full factor VIII activity and may affect the interaction of factor VIII with other components of the coagulation cascade.
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PMID:Identification and functional importance of tyrosine sulfate residues within recombinant factor VIII. 155 16

Glomus tumor of the skin and subcutis is an uncommon neoplasm in which the histologic features can be mimicked by other dermal lesions of diverse types. The cell of origin is thought by most to be the pericyte, which has some of the ultrastructural features of smooth muscle. We examined six glomus tumors with a panel of antibodies including the myogenic markers, muscle-specific actin (HHF-35), and desmin; all tumors were immunoreactive for muscle-specific actin, but only two expressed desmin. Half of these tumors expressed the endothelial determinant, factor VIII-related antigen. Pseudoangiomatous melanocytic nevi stimulating glomus tumors were consistently immunoreactive for S-100 protein, which was not expressed by glomus tumors.
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PMID:Cutaneous glomus tumor. A comparative immunohistochemical study with pseudoangiomatous intradermal melanocytic nevi. 184 11

Fourteen cases of naevocytic naevi with anastomising lacunae suggestive of vascular spaces are reported. The cells lining these lacunae were consistent with naevus cells, being positive for vimentin and S100 protein and negative for factor VIII-related antigen and Ulex europaeus I. The cells were not surrounded by laminin or type IV collagen. We suggest the formation of these vascular-like spaces may be due to defective production or increased degradation of components of the basement membrane with a consequent lack of cohesion.
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PMID:Naevocytic naevi with vascular-like spaces. 206 45

Factor VIII, a protein cofactor involved in blood coagulation, functions in vitro on a phospholipid membrane surface to greatly increase the rate of factor X activation by factor IXa. Using gel filtration, rapid sedimentation, and resonance energy transfer we have studied the interaction of recombinant-derived human factor VIII with small and large unilamellar phospholipid vesicles composed of phosphatidylserine and phosphatidylcholine. Resonance energy transfer, from intrinsic fluorophores in factor VIII to dansyl-phosphatidylethanolamine incorporated into vesicles, has been adapted for quantitative equilibrium measurements. Factor VIII binds rapidly and reversibly to small and large vesicles. At 8 degrees C the interaction of factor VIII with small vesicles fits a simple bimolecular model with a KD of 2 nM and a phospholipid binding site defined by 180 phospholipid monomers. At 25 degrees C the binding of factor VIII to small vesicles containing 20% phosphatidylserine can be described by an apparent KD of 4 nM; the phospholipid/protein ratio at saturation was 170. Binding to large vesicles was demonstrated with a KD of 2 nM and a phospholipid/protein ratio at saturation of 385. Binding was dependent upon the phosphatidylserine mole fraction and was nonlinear from 0 to 30% phosphatidylserine content. A direct comparison of factor VIII and factor V binding indicated that the affinity of factor V to phospholipid vesicles was equivalent to that of factor VIII and that the phosphatidylserine requirement was lower. A model is proposed to explain the nonlinear phosphatidylserine dependence of binding for factor VIII.
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PMID:Binding of human factor VIII to phospholipid vesicles. 210 32

So-called pseudovascular spaces, said to occur in 10% of benign pigmented nevi, are presumed to be shrinkage artifacts of tissue processing. In an attempt to characterize the cells lining these spaces, three benign pigmented nevi were studied with immunoperoxidase techniques. It was found that they stained positively with an anti-melanoma antibody, P97a (gamma-2a), but negatively with an antibody against an antigen-related factor VIII, which is a marker for vascular endothelium. We conclude that these spaces are lined by melanocytes of nevi and that the spaces are not truly vascular. In one specimen, the spaces were filled with erythrocytes, which suggest that the spaces were present before fixation. It has been suggested, though, that altered collagen and elastic tissue and the nevi themselves may diminish the resistance of the dermis to the mechanical stress of the biopsy procedure, which results in the formation of these spaces.
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PMID:Identification of cells lining pseudovascular spaces of benign pigmented nevi. 608 57

The low level of enzymatic activity of certain alpha 2-macroglobulin-proteinase complexes could be important to the function of factor VIII/von Willebrand glycoprotein since it is especially sensitive to proteolytic cleavage. To test this possibility, complexes of alpha 2-macroglobulin with plasmin, trypsin, and thrombin were formed in at least a 2:1 molar ratio of alpha 2-macroglobulin:proteinase and tested for effects on the factor VIII procoagulant activity of the factor VIII/von Willebrand glycoprotein. Neither the alpha 2-macroglobulin-trypsin complex nor the alpha 2-macroglobulin-plasmin complex affected factor VIII procoagulant activity. The behavior of the alpha 2-macroglobulin-thrombin complex was different. When alpha 2-macroglobulin and thrombin were incubated in a mole ratio of 3:1 or less, factor VIII procoagulant activity was enhanced to about the same extent as with free thrombin. Even at a 24:1 mole ratio, the mixture could produce 45% of the increase in factor VIII activity obtained with free thrombin. The isolated alpha 2-macroglobulin-thrombin complex could also activate the factor VIII procoagulant function to about 45% of the level obtained with an identical amount of uncomplexed thrombin. Analysis of the alpha 2-macroglobulin-125I-labeled thrombin complexes by rechromatography or by polyacrylamide gel electrophoresis in sodium dodecyl sulfate indicated that this activation was not due to free thrombin. We conclude that the alpha 2-macroglobulin-thrombin complex retains sufficient proteolytic activity to activate the procoagulant function of factor VIII/von Willebrand glycoprotein despite the latter being a very large substrate, having an estimated molecular weight of 1-20 million.
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PMID:Proteolytic activity of alpha 2-macroglobulin-enzyme complexes toward human factor VIII/von Willebrand factor. 618 90

We studied the effect of acute exercise on the ability of thrombin to activate plasma factor VIII (FVIII) activity in 20 healthy males. The subject showed an average exercise-related increase in FVIII activity of 54.5 +/- 8.2% over pre-exercise FVIII activity (p less than 0.001). When exposed to the same concentration of thrombin, post-exercise FVIII activity showed greater enhancement than pre-exercise FVIII activity: 157.1 +/- 12.8% increase in activity versus 117.3 +/- 9.9%, respectively (p less than 0.01). The degree of the potentiated thrombin effect in post-exercise samples relative to pre-exercise samples was linearly correlated with the degree of the exercise-related increase in FVIII activity. Taken together with our previous observations that the extent of thrombin enhancement of FVIII activity varies inversely with the mole ratio of FVIII/von Willebrand factor subunits to thrombin, these findings imply that release of FVIII does not occur during exercise, and that the exercise-related increase in FVIII activity results primarily, if not completely, from activation of already circulating but inactive FVIII.
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PMID:The basis for the increase in factor VIII procoagulant activity during exercise. 640 98

The possible role of Ca2+ as an essential constituent part of the human factor VIII complex has been investigated by stability studies, metal determinations, and gel filtration experiments. In citrated plasma, the factor VIII coagulant activity (VIII:C) deteriorated during storage in a biphasic manner. Collection of blood in heparin, instead of chelating anticoagulants, or neutralization of citrate by addition of CaCl2 to heparinized citrate phosphate dextrose (CPD) plasma rendered VIII:C noticeably stable. At physiologic levels of ionized calcium, VIII:C was almost completely stable during incubation of plasma for 6 hr at 37 degrees C. The influence of other divalent ions was also studied. Highly purified factor VIII complex was subjected to atomic absorption spectrophotometric analysis and found to contain about 1.0 mole calcium per 220,000 daltons. This intrinsic calcium could be readily removed by EDTA. When heparin plasma and CPD plasma were chromatographed on Sepharose CL-6B at 37 degrees C, all the factor-VIII-related activities eluted together as large protein complexes. In contrast, factor VIII coagulant antigen (VIII:CAg) and factor-VIII-related antigen (VIIIR:Ag) were completely dissociated upon exposure to EDTA. From these observations it is concluded that human factor VIII circulates in normal plasma as a calcium-linked protein complex.
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PMID:Human factor VIII: a calcium-linked protein complex. 641 52

Angiogenesis in malignant melanoma (MM) was evaluated by comparing mean vessel number (MVN) in Spitz's nevi (SN), thick and thin MMs that metastasized, and thick and thin MMs with > or = 10-year survival. Vessels were identified with antibodies against factor VIII-related antigen (FVIII) and CD34 in 37 MMs (17 < or = 1.9 mm and 20 > or = 4.0 mm) with > or = 10-year follow-up and 10 SN from children (< or = 9 years old). Fields (x250) with the highest vessel density were counted by independent observers blinded to clinical outcome. There were no differences in MVN between SN versus MMs (P = 1.0), but the distribution of vessels was much more uniform in SN. Seven MM pairs (> or = 5.5 mm) and five pairs (< or = 0.75 mm) were matched by sex, age, site, stage, and primary treatment (paired t-test). In the pairs > or = 5.5 mm, there was no correlation with MVN with either metastasis or death (FVIII P = 0.98; CD34 P = 0.85). Among the thin paired lesions, high MVN (FVIII = 46, CD34 = 39) was significantly related not only to metastasis (FVIII P = 0.04, CD34 P = 0.03) but also to death (FVIII P = 0.04, CD34 P = 0.05). MVN does not separate SN versus MM nor predict outcome in thick (> or = 4.0 mm) MMs; however, high MVN (> or = 42 average) is predictive of metastasis and death in MMs < or = 0.75 mm. Larger matched studies are indicated to confirm this observation.
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PMID:Extent of vascularization as a prognostic indicator in thin (< 0.76 mm) malignant melanomas. 752 76

Synthetic membranes of phosphatidylcholine require inclusion of at least 5% phosphatidylserine (Ptd-L-Ser) to form binding sites for factor VIII. The relatively high requirement for Ptd-L-Ser suggests that stimulated platelets may contain another membrane constituent that enhances expression of factor VIII-binding sites. We report that phosphatidylethanolamine (PE), which is exposed in concert with Ptd-L-Ser in the course of platelet stimulation, induces high affinity binding sites for factor VIII on synthetic membranes containing 1-15% Ptd-L-Ser. The affinity of factor VIII for binding sites on membranes of Ptd-L-Ser/PE/phosphatidylcholine in a 4:20:76 ratio was 10.2 +/- 3.5 nM with 180 +/- 33 phospholipid molecules/site. PE did not induce binding sites on membranes of 4% Ptd-D-Ser, indicating that the induced binding sites require the correct stereochemistry of Ptd-L-Ser as well as PE. Egg PE and dimyristoyl-PE were equivalent for inducing factor VIII-binding sites, indicating that hexagonal phase-inducing properties of PE are not important. We conclude that PE induces high affinity factor VIII-binding sites on membranes with physiologic mole fractions of Ptd-L-Ser, possibly including those of stimulated platelets.
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PMID:Phosphatidylethanolamine induces high affinity binding sites for factor VIII on membranes containing phosphatidyl-L-serine. 762 78


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