Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Class II MHC (Ia) molecules have been shown to be critical as restriction elements in the T helper/inducer cell recognition of antigen. Efforts to determine the role of allelic variation in MHC restricted antigen presentation have included the use of serologically selected mutants to correlate structural variations in Class II molecules with changes in the antigen presenting function of Ia bearing cells. Such studies have revealed that serologically selected mutations tend to occur in a single immunodominant region and that even a single amino acid substitution can alter T cell recognition of Ia molecules. We report here the characterization of two more serologically selected Class II A beta chain mutations. Each is due to a single base change which alters a single amino acid. One of these mutations is in the third hypervariable region (amino acid 64--glutamine to arginine) and alters the antigen presenting function. The second mutation at amino acid 48, though a relatively non-conservative change (arginine to cysteine), has no effect on APC phenotype. Such a result would be predicted based on comparisons made with the proposed three dimensional crystallographic structure of Class I molecules and models proposed for Class II molecules based on Class I structure. The amino acid change at position 48 is in a portion of the molecule that is most likely unavailable to bind antigen or interact with T cell receptor whereas the mutation at amino acid 64 is on an exposed face of the alpha helix, a region which could affect interaction with either antigen and/or the T cell receptor.
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PMID:Functional and molecular characterization of I-A kappa beta mutants is consistent with the predicted three dimensional structure of class II MHC molecules. 239 36

Aberrations of the APC gene, which plays an important role in the genesis of familial adenomatous polyposis and colorectal carcinoma, were investigated in 31 surgical specimens of primary breast carcinoma. These studies utilized the polymerase chain reaction followed by restriction-fragment-length polymorphism and single-strand-conformation polymorphism analyses combined with tumor cell enrichment by cell sorting. Loss of heterozygosity at the APC locus was detected in 8 (38%) of 21 informative cases, but only 2 (6%) of 31 tumors carried a mutated APC gene. Direct DNA sequencing analysis confirmed mutations at codon 1081 (AGC to ATC) resulting in an amino acid substitution of serine for isoleucine, and at codon 1096 (CAG to CAT) resulting in a substitution of glutamine for histidine. There were no significant correlations between the loss of heterozygosity or mutation at the APC locus and any clinicopathological characteristics. Our present observations suggest that the mutations of the APC gene may play an important role in the genesis of certain breast carcinomas, and that another tumor-suppressor gene, which is the true target of frequent loss of heterozygosity, may exist near the APC gene.
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PMID:Aberrations of the APC gene in primary breast carcinoma. 779 98

Activated protein C resistance (APCR) or Factor V Leiden has been recently described as the most prevalent hemostatic abnormality associated with venous thrombosis. In patients with familial thrombophilia, the prevalence of APCR is 19-60% and around 20% in sporadic venous thrombosis. APCR is usually measured by the degree of prolongation of Activated Partial Thromboplastin Time (APTT) on patient's plasma, induced by addition of APC in comparison to normal plasma. At the molecular level the defect is caused by a single-point mutation in the gene for factor V (FV) (G1.691-->A), that predicts the replacement of Arg506 by Glutamine. This mutation makes activated factor V resistant to inactivation by APC. Since the prevalence of the defect is highly variable among different populations, the objective of this work was to study its frequency in our population and in patients with thrombophilia. We defined the normal range for APTT ratio (APTT + APC/APTT - APC) in a group of 73 healthy volunteers in whom the presence of FV Q506 mutation was searched using Mull enzyme digestion of PCR amplified genomic fragment containing the nucleotide 1.691. The lower limit of APTT ratio established in this group was 2.13. APCR was found in 6 out of 159 control subjects (3.8%) and in 14/50 (28%) of patients with thrombosis. In 13 cases as a single defect and in one associated to type I protein C deficiency. All the APCR patients and control subjects were heterozygotes by gene analysis. The results demonstrate that in our population APCR is also the most common defect associated with thrombosis, in accordance with a high prevalence in the population. The ability to screen for this defect will permit the identification of carriers that would benefit of preventive therapy at risk situations.
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PMID:[Activated C protein resistance: laboratory study and prevalence of the defect in the Chilean population]. 904 21

Protein C (PC) is the key component of a natural anticoagulant pathway that is activated on the surface of endothelial cells by thrombin bound to thrombomodulin. Activated protein C [APC] cleaves and inhibits membrane bound factor Va and factor VIIIa, which leads to specific and efficient downregulation of the coagulation pathway. In these reactions, protein S (PS) and intact factor V (FV) function as cofactors to APC. Inherited deficiencies of PC, PS, or antithrombin were until recently the major genetic causes of familial venous thrombophilia, but they were found in less than 5% to 10% of patients with thrombosis. The situation changed dramatically with the description in 1993 of resistance to APC as a major risk factor for venous thrombosis. Inherited APC resistance, which is found in 20% to 60% of patients with venous thrombosis, is caused by a single point mutation in the FV gene predicting substitution of arginine [R] at position 506 with a glutamine (Q). The mutation, which is the result of a founder effect, is common in Caucasians with 1% to 15% prevalence in the population, whereas it is not found in other human races. Mutated FV (FVR506Q, FV:Q506 or FV Leiden) has normal procoagulant properties but shows partial resistance to APC, which results in a hypercoagulable state conferring a lifelong increased risk of thrombosis. As a result of its high prevalence, the FV mutation is not uncommon among patients with other inherited defects such as deficiency of PS, PC, or antithrombin. Those having combined defects have a higher incidence of thrombosis, and it is now recognized that severe thrombophilia is a typical multigenetic disease. The high prevalence of the FVR506Q mutation and the availability of easy functional and genetic tests will profoundly influence the development of therapeutic and prophylactic regimens and will probably result in a decreased incidence of thromboembolic events.
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PMID:Resistance to activated protein C as risk factor for thrombosis: molecular mechanisms, laboratory investigation, and clinical management. 924 7

We have isolated, mapped and sequenced the 5' promoter region of the human SH3BGR (SH3-Binding Glutamine Rich) gene located in the Down syndrome region-2, between markers D21S55 and MX1 of human chromosome 21. This region has been postulated as the minimal region for congenital heart disease and 6 facial and dermatoglyphic features present in Down syndrome. The SH3BGR gene is expressed in fetal and adult heart and in skeletal muscle and therefore it is a candidate gene for the congenital heart defect and muscle hypotonia. The 5' region of the gene has been positioned in a 115 kb PAC/cosmid contig with full EcoRI/SmaI restriction map covering cosmid pockets 122-123 as well as cosmid pocket 124 located between markers D21S268 and D21S220. Sequencing of the SH3BGR promoter region has allowed the identification of several potential regulatory elements of this candidate gene for the congenital heart disease and other potential DS features. Several of the elements identified are also present in other muscle-expressed genes.
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PMID:High-resolution physical map and identification of potentially regulatory sequences of the human SH3BGR located in the Down syndrome chromosomal region. 942 70

Activated protein C resistance is an inherited thrombophilia caused by a point mutation in the factor V gene (G to A transition in nucleotide 1691 in the factor V gene with replacement of arginine (R) 506 by glutamine (Q) in the factor V molecule). The mutation is commonly named factor V R506Q or factor V Leiden. The mutation results in a poor anticoagulant response to activated protein C. APC resistance is inherited autosomally, and approximately 5-10% of the Norwegian population are carriers of the mutation. It is present in 20-50% of all cases of venous thromboembolism. Among asymptomatic heterozygous family members of affected individuals there is a five to eight-fold increase in the risk of venous thromboembolism, whereas there may be a 100-fold increased risk among homozygous individuals. The risk for asymptomatic carriers without a family history is yet not known. Activated protein C resistance is a major risk factor for venous thromboembolism, and the detection of activated protein C resistance is vital for proper prophylaxis and treatment of this disorder. It is essential therefore that as many medical specialists as possible acquire knowledge of activated protein C resistance. This report describes a family with activated protein C resistance and the main indications for screening for inherited thrombophilia.
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PMID:[Activated protein C resistance--a recently discovered hereditary thrombophilia]. 982 2

Background: Resistance to activated protein C(APC) is the most prevalent identifiable risk factor for inherited thrombophilia. Over 90% of APC resistance results from a single point mutation in the Factor V gene. The mutation, termed FV R506Q of FV Leiden, predicts an abnormal Factor Va protein in which arginine, at amino acid position 506, is replaced by glutamine, rendering Factor Va resistant to proteolytic inactivation by APC, thus establishing a life long hypercoagulable state. The current study compared three different polymerase chain reaction (PCR)-based approaches for the detection of FV R506Q. Methods and Results: Sixty-seven patient blood samples were genotyped by (1) analyzing for loss of a Mnl I recognition site, an acquired restriction-fragment-length polymorphism (RFLP) due to FV R506Q; (2) primer-engineered RFLP wherein the presence of FV R506Q results in generation of a novel Nla III recognition site; and (3) allele-specific PCR. Sixty-five of 67 patient samples yielded concordant genotype results by all three PCR methods. Of the remaining 2 of the 67 patients, a "nondiagnostic" result was obtained for either allele-specific PCR or primer-engineered RFLP. Conclusions: A comparative analysis of 67 patient samples demonstrated that primer engineered RFLP and allele-specific PCR offer feasible alternative or confirmatory testing approaches to Mnl I RFLP for the detection of FV R506Q. A high degree of diagnostic concordance was observed for all three methods, and no false positive or negative results were observed with the Mnl I RFLP technique.
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PMID:Resistance to Activated Protein C: Comparison of Three Different PCR Methods for Detection FV R506Q. 1046 76

masterblind (mbl) is a zebrafish mutation characterised by the absence or reduction in size of the telencephalon, optic vesicles and olfactory placodes. We show that inhibition of Gsk3beta in zebrafish embryos either by overexpression of dominant negative dn gsk3beta mRNA or by lithium treatment after the midblastula transition phenocopies mbl. The loss of anterior neural tissue in mbl and lithium-treated embryos is preceded by posteriorization of presumptive anterior neuroectoderm during gastrulation, which is evident from the anterior shift of marker genes Otx2 and Wnt1. Heterozygous mbl embryos showed increased sensitivity to inhibition of GSK3beta by lithium or dn Xgsk3beta that led to the loss of eyes. Overexpression of gsk3beta mRNA rescued eyes and the wild-type fgf8 expression of homozygous mbl embryos. emx1 that delineates the telencephalon is expanded and shifted ventroanteriorly in mbl embryos. In contrast to fgf8, the emx1 expression domain was not restored upon overexpression of gsk3beta mRNA. These experiments place mbl as an antagonist of the Wnt pathway in parallel or upstream of the complex consisting of Axin, APC and Gsk3beta that binds and phosphorylates beta-catenin, thereby destabilising it. mbl maps on LG 3 close to a candidate gene axin1. In mbl we detected a point mutation in the conserved minimal Gsk3beta-binding domain of axin1 leading to a leucine to glutamine substitution at position 399. Overexpression of wild-type axin1 mRNA rescued mbl completely, demonstrating that mutant axin1 is responsible for the mutant phenotype. Overexpression of mutant L399Q axin1 in wild-type embryos resulted in a dose-dependent dominant negative activity as demonstrated by the loss of telencephalon and eyes. We suggest that the function of Axin1/Mbl protein is to antagonise the Wnt signal and in doing so to establish and maintain the most anterior CNS. Our findings provide new insights into the mechanisms by which the Wnt pathway generates anteroposterior polarity of the neural plate.
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PMID:Ectopic Wnt signal determines the eyeless phenotype of zebrafish masterblind mutant. 1164 Dec 13

APC (activated Protein C) inactivates human Factor VIIIa following cleavage at residues Arg336 and Arg562 within the A1 and A2 subunits respectively. The role of the P1 arginine in APC-catalysed inactivation of Factor VIIIa was examined by employing recombinant Factor VIIIa molecules where residues 336 and 562 were replaced with alanine and/or glutamine. Stably expressed Factor VIII proteins were activated by thrombin and resultant Factor VIIIa was reacted at high concentration with APC to minimize cofactor inactivation due to A2 subunit dissociation. APC cleaved wild-type Factor VIIIa at the A1 site with a rate approximately 25-fold greater than that for the A2 site. A1 mutants R336A and R336Q were inactivated approximately 9-fold slower than wild-type Factor VIIIa, whereas the A2 mutant R562A was inactivated approximately 2-fold slower. No cleavage at the mutated sites was observed. Taken together, these results suggested that cleavage at the A1 site was the dominant mechanism for Factor VIIIa inactivation catalysed by the proteinase. On the basis of cleavage at Arg336, a K(m) value for wild-type Factor VIIIa of 102 nM was determined, and this value was significantly greater than K(i) values (approximately 9-18 nM) obtained for an R336Q/R562Q Factor VIIIa. Furthermore, evaluation of a series of cluster mutants in the C-terminal region of the A1 subunit revealed a role for acidic residues in segment 341-345 in the APC-catalysed proteolysis of Arg336. Thus, while P1 residues contribute to catalytic efficiency, residues removed from these sites make a primary contribution to the overall binding of APC to Factor VIIIa.
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PMID:Role of P1 residues Arg336 and Arg562 in the activated-Protein-C-catalysed inactivation of Factor VIIIa. 1650 79

Cell proliferation is accompanied by an increase in the utilization of glucose and glutamine. The proliferative response is dependent on a decrease in the activity of the ubiquitin ligase anaphase-promoting complex/cyclosome (APC/C)-Cdh1 which controls G1-to-S-phase transition by targeting degradation motifs, notably the KEN box. This occurs not only in cell cycle proteins but also in the glycolysis-promoting enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase isoform 3 (PFKFB3), as we have recently demonstrated in cells in culture. We now show that APC/C-Cdh1 controls the proliferative response of human T lymphocytes. Moreover, we have found that glutaminase 1 is a substrate for this ubiquitin ligase and appears at the same time as PFKFB3 in proliferating T lymphocytes. Glutaminase 1 is the first enzyme in glutaminolysis, which converts glutamine to lactate, yielding intermediates for cell proliferation. Thus APC/C-Cdh1 is responsible for the provision not only of glucose but also of glutamine and, as such, accounts for the critical step that links the cell cycle with the metabolic substrates essential for its progression.
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PMID:Anaphase-promoting complex/cyclosome-Cdh1 coordinates glycolysis and glutaminolysis with transition to S phase in human T lymphocytes. 2104 50


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