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Query: UNIPROT:P06889 (Mol)
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In the previous paper in this series, we described a form of self-reactivity among T cells called the "syngeneic T-T lymphocyte reaction" (STTLR). The phenomenon involves responder T cells that are stimulated to proliferate by irradiated antigen or self-reactive cloned T cell lines. The proliferative STTLR occurs in cultures rigorously depleted of conventional APC and is inhibitable by anti-Ia antibodies of the appropriate specificity. We also showed that both L3T4+ Lyt2- and L3T4- Lyt2+ T cell subsets participate in the STTLR-induced by the IEk-specific Lbd T cell line. In this paper, we report our studies on the effector phase of STTLRs, in particular, the cytotoxic responses induced by Lbd cells. We demonstrate that uncloned and cloned lines (called Dbl) of anti-Lbd cytotoxic cells are L3T4- Lyt2+ effector cells that kill Lbd, antigen-reactive T cells, and syngeneic B cells stimulated with LPS. They also kill syngeneic splenic cells stimulated with Con A for 72 h or less; longer culture periods in the presence of Con A yield Dbl-resistant T cells. Resting T cells are also resistant to Dbl cells. Using LPS-induced splenic B cells from H-2 congenic mice, we map the anti-self specificity of uncloned and cloned anti-Lbd cells to the Kk + IAk regions of the MHC. Seemingly concordant results were obtained using L transformants expressing IAk molecules on their surface. However, control studies with fibroblast lines and UV-induced fibrosarcoma cells unexpectedly revealed a high susceptibility to lysis by Dbl cells among certain Ia- cell lines. These results suggested that the antigen recognized by Dbl cells is not IAk itself but either an MHC-encoded or MHC-regulated gene product expressed by activated T and B cells and certain tumor cells. The target antigen is important in immunoregulation because Dbl cells suppress both the proliferation of Lbd cells to syngeneic cells and primary T cell-dependent anti-SRC PFC responses. From an immunoregulatory viewpoint, the existence of Lbd-Dbl cells offers several appealing features. Since Lbd cells cannot activate resting B cells or replace antigen-specific helper cells, they cannot initiate immune responses nonspecifically. In the presence of the appropriate antigen-specific helper T cells, Lbd and other self-reactive cells can amplify an immune response and thus facilitate its exponential growth. Since the self-reactive cells activate the Dbl cytotoxic circuit described above, they also provide the stimulus required to terminate immune responses quickly.(ABSTRACT TRUNCATED AT 400 WORDS)
J Mol Cell Immunol 1986
PMID:The syngeneic T-T lymphocyte reaction (STTLR). II. Induction of primary T anti-T cell cytotoxic responses in vitro in T cell cultures stimulated with syngeneic self-reactive T cells. 350 19

Gamma-carboxyglutamic acid is an amino acid with a dicarboxylic acid side chain. This amino acid, with unique metal binding properties, confers metal binding character to the proteins into which it is incorporated. This amino acid has been discovered in blood coagulation proteins (prothrombin, Factor X, Factor IX, and Factor VII), plasma proteins of unknown function (Protein C, Protein S, and Protein Z), and proteins from calcified tissue (osteocalcin and bone-Gla protein). It has also been observed in renal calculi, atherosclerotic plaque, and the egg chorioallantoic membrane, among other tissues. Gamma-carboxyglutamic acid is synthesized by the post-translational modification of glutamic acid residues. This reaction, catalyzed by a hepatic carboxylase, requires reduced vitamin K, oxygen, and carbon dioxide. The function of gamma-carboxyglutamic acid is uncertain. In prothrombin gamma-carboxyglutamic acid residues bound to metal ions participate as an intramolecular non-covalent bridge to maintain protein conformation. Additionally, these amino acids participate in the calcium-dependent molecular assembly of proteins on membrane surfaces through intermolecular bridges involving gamma-carboxyglutamic acid and metal ions.
Mol Cell Biochem 1981 Sep 25
PMID:Gamma-carboxyglutamic acid. 645 61

More than half of all patients with familial or recurring venous thrombosis have hereditary resistance to activated protein C (HRAPC) as the result of specific missense mutation in the gene for coagulation factor V. Because the mutant factor Va (with an Arg to Gln substitution at codon 506) cannot be cleaved and inactivated by activated protein C, carriers of this mutation are at significantly increased risk of venous thrombosis. We have recently introduced a direct polymerase chain reaction (PCR)-based clinical diagnostic test for the factor V codon 506 mutation based on the destruction of an Mnl I restriction site by the causative nucleotide substitution. To assess the accuracy of this PCR-based assay, we compared a functional clotting time test for HRAPC with the direct mutation test. Of 47 patients dually tested, only five had discrepant values for the functional test versus the DNA test. Either of these two complementary assays is useful for the accurate diagnosis of HRAPC. The DNA-based test is, however, specifically recommended for evaluation of anticoagulated patients or patients with borderline functional tests and confirmation of genotype in HRAPC families. In an additional analysis of 287 normal individuals, we found an extremely high prevalence of the mutated codon 506 allele-- approximately 4% in each of two different populations. The absence of disease in the majority of heterozygous carriers suggests that symptomatic thrombosis requires the simultaneous presence of both a mutated factor V protein and additional synergistic factors.
Diagn Mol Pathol 1995 Sep
PMID:Molecular detection of a common mutation in coagulation factor V causing thrombosis via hereditary resistance to activated protein C. 749 38

Surfactant protein C (SP-C), a 3.7-kDa hydrophobic lung-specific protein, is synthesized and secreted by pulmonary type II cells through proteolytic processing of a 21-kDa propeptide (SP-C21) by currently undefined pathways. Previously, we reported the production of a polyclonal antibody against rat SP-C21 (anti-CPROSP-C) using a synthetic peptide as the immunizing antigen (Beers, M. F., Wali, A., Eckenhoff, M. E. F., Feinstein, S., Fisher, J. H., and Fisher, A. B. (1992) Am. J. Respir. Cell. Mol. Biol. 7, 368-378). In this study, two additional epitope-specific proSP-C antibodies produced using synthetic peptide sequences were utilized to examine synthetic processing of SP-C. Anti-NPROSP-C (Met10-Gln23) and anti-CTERMSP-C (Ser149-Ser166) recognized native proSP-C21 produced from in vitro translation of SP-C cDNA. Immunocytochemistry using anti-NPROSP-C confirmed the localization of proSP-C peptides exclusively in type II cells. Western analysis of subcellular fractions identified a single 21-kDa band in microsomes and a 16-kDa form in lamellar bodies each recognized by all three antisera, while anti-NPROSP-C also uniquely identified a prominent 5-6-kDa form in lamellar bodies. In a perfused rat lung model labeled with [35S]cysteine/methionine, immunoprecipitation of lung homogenate and lamellar body fractions identified early appearances of 35S-labeled 21-, 18-, and 16-kDa SP-C forms in homogenate and a 16-kDa intermediate form in lamellar bodies. Anti-NPROSP-C also exclusively detected time-dependent appearances of 5-10-kDa proSP-C forms in lamellar bodies and homogenates. Processing of proSP-C21 was completely blocked by inclusion of brefeldin A (15 micrograms/ml) in the perfusate. These results demonstrate that synthetic peptides can be used to produce epitope-specific antisera which recognize more hydrophilic domains of proSP-C and show that proSP-C processing occurs intracellularly in subcellular compartments of type II cells which are distal to the trans-Golgi network.
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PMID:Localization, synthesis, and processing of surfactant protein SP-C in rat lung analyzed by epitope-specific antipeptide antibodies. 751 6

Nitrogen regulatory protein C (NtrC) is a bacterial enhancer-binding protein that activates transcription by the sigma 54-holoenzyme. To activate transcription, NtrC must hydrolyze ATP, a reaction that depends upon its being phosphorylated and forming an appropriate oligomer. In this paper we characterize "constitutive" mutant forms of the NtrC protein from Salmonella typhimurium; unlike wild-type NtrC, these forms are able to hydrolyze ATP and activate transcription in vitro without being phosphorylated. The amino acids altered in NtrCconstitutive proteins are located in both the N-terminal regulatory domain and the central domain, which is directly responsible for transcriptional activation. The residues that are altered are not conserved among activators of the sigma 54-holoenzyme, and are not identical even among NtrC proteins from members of different subgroups of the proteobacteria (purple bacteria). NtrCconstitutive proteins are phosphorylated normally; phosphorylation increases their ability to hydrolyze ATP and activate transcription. Moreover, the oligomerization of these proteins that occurs when they bind to an enhancer also increases the ATPase activity of both unmodified and phosphorylated forms. Removal of the N-terminal regulatory domain from two NtrCconstitutive proteins with amino acid substitutions in the central domain (NtrCS160F and NtrCV2881) leaves them active, indicating that essential oligomerization determinants lie outside the regulatory domain. This conclusion is confirmed by the observation that the ATPase activity of delta N-NtrCS160F is greatly stimulated when it binds to an enhancer, and by the ability of this protein to activate transcription synergistically with a form of NtrC incapable of DNA-binding. Together with previous results indicating that oligomerization determinants do not lie in the C-terminal DNA-binding domain of NtrC; these results provide evidence that they lie in the central domain.
J Mol Biol 1995 Jun 16
PMID:Constitutive forms of the enhancer-binding protein NtrC: evidence that essential oligomerization determinants lie in the central activation domain. 760 83

Two kinds of proteinases, type-I and type-II, were purified or partially purified from salted muscle of anchovy, Engraulis japonica. Mol. wts. of type-I and type-II proteinases were estimated to 25,000 and 37,000, respectively, on electrophoretic analysis. Both proteinases strongly hydrolyzed synthetic tri or tetrapeptide substrates specific to trypsin, alpha-thrombin, and an activated protein C, while they hardly hydrolyzed Arg-MCA and benzoyl Arg-MCA derivatives. The proteinases were inhibited by common trypsin inhibitors. Optimal pH for the proteinase activities were pH 6.8 (type-I) and pH 7.0 to 7.5 (type-II), and the proteinases showed the highest activities at 45 degrees C (type-I) and 50 degrees C (type-II). The N-terminal amino acid sequence of type-I proteinase, 1I-2V-3G-4G ... (29 residues were identified), was significantly similar to sequences of trypsins and tryptases. Based on these findings, both proteinases were presumed to be kinds of tryptases in E. japonica muscle.
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PMID:Two kinds of neutral serine proteinases in salted muscle of anchovy, Engraulis japonica. 761 98

Patients with liver failure can present both thrombotic and hemorrhagic complications because of the deficiency in coagulation factors and inhibitors (protein C and S, antithrombin III) and impairment of fibrinolytic balance. Here we report the case of a 63-year-old man with liver cirrhosis, recurrent thrombosis, and features of low-grade consumption coagulopathy, showing severe antithrombin III deficiency (about 30% of normal values). Treatment with antithrombin III (2000 U/day) and low doses of heparin (5000 U b.i.d.) was successful in modulating the coagulation system toward an antithrombotic effect. After discharge from hospital the ambulatory treatment with antithrombin III concentrates (2000 U twice a week) allowed the attainment of antithrombin III activity of about 60% and prevented the patient from recurrence of venous thrombosis.
J Mol Med (Berl) 1995 Feb
PMID:Modulation of hemostatic balance with antithrombin III replacement therapy in a case of liver cirrhosis associated with recurrent venous thrombosis. 762 35

Prolactin-like protein C (PLP-C) is a major rat placental protein which is expressed during the second half of pregnancy and belongs to the growth hormone-prolactin family. Here we report on the isolation of overlapping rat placental cDNAs which specify a transcript of 915 base pairs and predict a 205-amino acid translated product. The full-length cDNA shares 93% homology with the nucleotide sequence reported for PLP-C, and the putative protein, which we designate PCRP (prolactin-like protein C-related protein), exhibits 88% homology with the PLP-C precursor protein. PCRP lacks the signal sequence and the first 2 N-terminal cysteine residues present in PLP-C. Northern blot analysis indicated the basal zone-specific expression of PCRP mRNA, with no detectable expression in decidua and labyrinth. Southern blot analysis of rat genomic DNA using PCRP cDNA as a probe demonstrated multiple hybridization bands, suggestive of a family of genes encoding prolactin-like proteins. Western immunoblot analysis of basal zone culture media using a PCRP antipeptide antiserum revealed at least 5 immunoreactive proteins. The existence of a PLP-C family of proteins in rat placenta after midpregnancy suggests their functional significance in the maintenance of pregnancy and fetal development.
Mol Reprod Dev 1995 Jun
PMID:Cloning of a novel rat placental prolactin-like protein C-related cDNA. 765 70

The MHC class II molecules bind antigenic peptides and present them to T cells. Their ability to carry out these functions depends, in a critical way, on the detailed structure of the membrane-distal alpha 1 and beta 1 domains of these molecules. Using the I-Ak molecule and a series of hen egg lysozyme (HEL) peptide-specific, I-Ak-restricted T cell hybridomas as a model, we have examined the effect of altering essentially all of the polymorphic residues of the murine class II molecule on its ability to present Ag. Our results support the following conclusions: (1) both the location and the structural alteration introduced in a specific amino acid interchange are important in determining the effect the interchange will have on Ag presentation; and (2) changes in amino acids in the floor of the putative Ag binding cleft of the class II molecule can exert a major influence on the presentation of peptides to T cells. By carrying out direct binding experiments between the HEL(46-61) peptide and two mutant I-A molecules that fail to present HEL(46-61) to appropriate T cells, we were able to assess, in a quantitative fashion, the role played by peptide binding in the failure to present Ag. Our results suggest that, in the two cases studied, the failure to bind the HEL(46-61) peptide was not primarily responsible for the failure of the mutant class II molecule to present that peptide. Specifically, an A beta chain mutant that possesses d allelic residues at positions 65-67 in the second PMR of the Ak beta chain actually binds HEL(46-61) at wild type (I-Ak) levels. In contrast, an A alpha chain chimera in which b allelic residues are inserted in the third PMR of the Ak alpha chain, binds HEL(46-61) about three- to four-fold less well than wild type. While this decrease in binding affinity may be partially responsible for the inability of the latter chimeric molecule to present HEL(46-61), it can not be the total explanation because increasing the peptide concn even by an order of magnitude does not restore Ag presentation by APC expressing this chimeric molecule. These results are discussed in terms of the currently accepted model of the class II molecule.
Mol Immunol 1993 Apr
PMID:Functional analysis of the antigen binding region of an MHC class II molecule. 768 33

The stability of certain dicentric chromosomes in humans seems to result from inactivation of one centromere, yielding a functionally monocentric chromosome. Centromere protein C (CENP-C) was previously shown to be present at active centromeres but absent from the inactive centromere of one homologous dicentric rearrangement. We have combined indirect immunofluorescence detection of CENP-C and fluorescence in situ hybridization with chromosome-specific alpha-satellite DNA probes in a simultaneous assay to unequivocally identify the active and inactive centromeres of a dicentric (X;15) translocation. In both fibroblast and lymphoblast cell lines containing the translocation, the X chromosome centromere consistently had a primary constriction and CENP-C immunofluorescence, and is therefore the active centromere. CENP-C was never detected at the chromosome 15 centromere, which appears to be inactive. The inactivation pattern is apparently stable and observed in all cells with the translocation. Immunofluorescence with CREST serum revealed staining at both centromeres of the translocation, and thus was not specific to the active centromere. This study demonstrates the specificity of CENP-C to the active centromere in a non-homologous rearrangement and further establishes CENP-C as an essential component of a functional human centromere.
Hum Mol Genet 1995 Feb
PMID:Further evidence that CENP-C is a necessary component of active centromeres: studies of a dic(X; 15) with simultaneous immunofluorescence and FISH. 775 82


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