Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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We have studied mRNA expression for Class I HLA (human leukocyte antigen) on male germ cells by amplification of gene fragments in PCR technique and by Northern hybridization. RNA was extracted from fractionated gametogenic cells (isolated from testis) and reversely transcribed. Then, cDNA was amplified for specific HLA sequence (HLA, -A, -B, -C). The specificity of this product was confirmed in "nested" PCR of 400 bp gene fragment coding for alpha 2 domain, alpha 3 domain, and the transmembrane portion of Class I HLA. The results indicate minimal expression of classical Class I HLA on gametogenic cells. Northern hybridization with 669 bp cDNA fragment (spanning for alpha 3 domain, transmembrane, cytoplasmic, and 3' untranslated region) resulted in a low intensity signal from gametogenic cell fractions and confirmed our findings obtained by PCR. The minimal expression of classical HLA antigens may create a neutral cover for the male reproductive system, thereby preventing an immunological response during germ cell differentiation.
Mol Reprod Dev 1994 Jun
PMID:Analysis of mRNA for class I HLA on human gametogenic cells. 808 Jun 53

We previously reported that a gene in linkage disequilibrium with HLA-Bw54, DR4, and DRw53 might control the susceptibility to silicosis (K. Honda et al. 1988. N. Engl. J. Med. 319:1610). To further define the HLA-linked gene and other genetic factors for predisposition of silicosis, we determined for HLA-DQ and DP alleles using the polymerase chain reaction and sequence-specific oligonucleotide probes and made a restriction fragment length polymorphism (RFLP) analysis of the fourth component of complement (C4) genes, immunoglobulin lambda variable chain (IGLV) gene, and T-cell receptor alpha and beta genes in 46 Japanese patients with silicosis. The frequency of DQB1*0401 (relative risk [RR] = 2.2, P < 0.02) was increased and that of DQB1*0601 (RR = 0.36, P < 0.01) was decreased in the patients. RFLP analysis of C4 and IGLV genes showed significant association between silicosis and a specific RFLP pattern of C4A3-C4B5 allotype (RR = 2.3, P < 0.05) and that of IGLV 5.3 kb (RR = 0.33, P < 0.003). No other genetic markers showed significant association. Statistical analyses of the associated genetic markers revealed that the HLA-Bw54 was the allele that showed primary association with silicosis and the frequencies of the C4 and HLA-DQ alleles were suggested to be increased due to their linkage disequilibrium with the HLA-Bw54. We conclude that the major gene for silicosis may be mapped near the HLA-B locus.
Am J Respir Cell Mol Biol 1993 Jan
PMID:Immunogenetic analysis of silicosis in Japan. 809 41

The binding of a T cell-presented peptide to MHC class II alpha,beta chains occurs as a concurrent process with the release of the associated invariant chain (Ii) by cathepsin B. Ii was digested by cathepsin B from solubilized, MHC class II alpha,beta,Ii complexes in the presence of N-hydroxysuccinimidyl-4-azidobenzoate-conjugated, 125I-labeled, influenza virus matrix (18-29) peptide. The peptide was crosslinked where it became bound. This HLA-DR1-restricted peptide bound about three times more efficiently to class II alpha,beta chains of DR1-positive B cells when present during cathepsin B digestion of Ii than when added afterward, also at pH 5.0. Binding was competed by similarly DR-restricted peptides. Cathepsin D cleaved Ii but did not enhance peptide binding. However, a trace level of cathepsin D, added to the assay for peptide binding in the presence of cathepsin B, further enhanced peptide binding about three times. These experiments support an hypothesis for the staged release of Ii fragments by cathepsin D and cathepsin B, catalyzing at one point the insertion of a peptide into the antigen binding site formed by class II alpha and beta chains.
Mol Immunol 1994 Mar
PMID:More efficient peptide binding to MHC class II molecules during cathepsin B digestion of Ii than after Ii release. 813 80

Loss of HLA antigen expression is considered to be one of the mechanisms whereby tumor cells escape immune surveillance. We recently observed reduced or lost expression of HLA antigens during human colon carcinogenesis. We studied the effect of bile acids (BAs), long implicated in the pathogenesis of colon cancer, on the expression of HLA class I antigens in human colon adenocarcinoma cells. Lithocholic acid (LCA) decreased by 42% the expression of HLA class I antigens on the surface of these cells. This dose-dependent reduction was specific for both the target genes and the chemical structure of LCA, and was not evident in cultured liver cells. None of the other BAs that were tested manifested this effect. LCA, and to a lesser extent deoxycholic acid (DCA), decreased steady-state HLA class I mRNA levels. LCA decreased the rate of transcription of HLA-B (64%) and HLA-C (87%) but not HLA-A; DCA had a similar but less pronounced effect. In transient gene expression (CAT assays) experiments, we evaluated the role of a 0.6-0.7 kb EcoRI/XbaI sequence from the 5' flanking region of HLA-A2, -B7 and -Cw7 genes in the regulation of class I gene expression by LCA. LCA down-regulated by 70% the expression of the reporter gene for all three genes. We interpret these results as indicating a differential regulation of the three HLA loci by LCA. Our findings, demonstrating a profound effect of LCA on HLA class I gene regulation, raise the possibility that such a mechanism may be operative in vivo.
Mol Immunol 1994 Jun
PMID:Lithocholic acid inhibits the expression of HLA class I genes in colon adenocarcinoma cells. Differential effect on HLA-A, -B and -C loci. 819 71

The presentation by antigen-presenting cells of immunodominant peptide segments in association with major histocompatibility complex (MHC) encoded proteins is fundamental to the efficacy of a specific immune response. One approach used to identify immunodominant segments within proteins has involved the development of predictive algorithms which utilize amino acid sequence data to identify structural characteristics or motifs associated with in vivo antigenicity. The parallel-computing technique termed 'neural networking' has recently been shown to be remarkably efficient at addressing the problem of pattern recognition and can be applied to predict protein secondary structure attributes directly from amino acid sequence data. In order to examine the potential of a neural network to generalize peptide structural features related to binding within class II MHC-encoded proteins, we have trained a neural network to determine whether or not any given amino acid of a protein is part of a peptide segment capable of binding to HLA-DR1. We report that a neural network trained on a data base consisting of peptide segments known to bind to HLA-DR1 is able to generalize features relating to HLA-DR1-binding capacity (r = 0.17 and p = 0.0001).
J Mol Recognit 1993 Mar
PMID:Using a neural network to identify potential HLA-DR1 binding sites within proteins. 825 Nov 91

The cytokines tumor necrosis factor (TNF), beta interferon (IFN-beta), and IFN-gamma increase major histocompatibility complex class I molecule expression. A greater than additive (i.e., synergistic) induction of class I heavy-chain mRNA is observed in HeLa cells treated with TNF in combination with either type of IFN. To define the cis-acting elements mediating cytokine synergy, the promoter of a human major histocompatibility complex class I heavy-chain gene (HLA-B7) was placed in front of a reporter gene and transfected into HeLa cells. Deletion analysis mapped the elements required for synergy to a 40-bp region containing a kappa B-like element, which is necessary for the response to TNF, and an interferon consensus sequence (ICS), which is necessary for the responses to IFNs. When the orientation of these elements was reversed or their normal 20-bp spacing was reduced by 5 or 10 bp, i.e., one half or one full turn of the DNA helix, essentially equivalent responses were obtained, suggesting that these parameters are not critical. In electromobility shift assays, a p50-containing NF-kappa B nuclear factor from TNF-treated cells binds kappa B-containing probes, and ISGF-2 from IFN-gamma-treated cells binds ICS-containing probes. A probe containing both the kappa B and ICS elements (kappa B-ICS) forms a novel complex with nuclear factors isolated from cells treated with both TNF and IFN-gamma; this complex also forms when nuclear factors from individually cytokine-treated cells are mixed in vitro. The natural variant ICS found in HLA-A responds to IFN-gamma and can mediate synergy with TNF. However, the variant kappa B found in HLA-C does not respond to TNF, nor can it mediate synergy between TNF and IFN-gamma. These observations suggest that synergy between TNF and IFNs in the induction of HLA class I gene expression results from the sum of individual interactions of cytokine-activated enhancer-binding factors with the transcription initiation complex.
Mol Cell Biol 1994 Feb
PMID:HLA class I heavy-chain gene promoter elements mediating synergy between tumor necrosis factor and interferons. 828 10

Enhancer sequences of human papilloma virus (HPV) type 18 were used for screening of HeLa cells cDNA library in lambda gt11 using the protein binding method. Clones with YB I gene homology sequences were isolated. This gene is coding the protein which binds the regulatory region of Y gene of main histocompatibility complex (HLA 11). The YB I transcripts were revealed in all tested samples of cervical carcinomas. To analyze the protein the rabbit antibodies were produced to synthetic peptide, which corresponds to the most hydrophilic region of the protein. This antipeptide serum allowed to identify the nuclear 42K protein in HeLa cells as well as in normal fibroblasts.
Mol Biol (Mosk)
PMID:[In vivo identification of YB-1 protein, interacting with the enhancer of human papillomavirus (HPV) type 18, using antibodies to a synthetic peptide]. 838 54

The molecular basis of the differential specificity of seven mouse anti-id mAb elicited with the syngeneic anti-HLA-A2,28 mAb CR11-351 was analyzed by comparing their specificity with their heavy and light chain variable region sequences. Of the six mAb recognizing idiotopes within the antigen combining site of mAb CR11-351, mAb T10-352, T10-440 and T10-505 recognize the same (or spatially close) idiotope(s) since they cross-inhibit each other in their binding to mAb CR11-351 and elicit syngeneic anti-anti-id antibodies with similar specificity. On the other hand, mAb T10-421, T10-649 and T10-938 appear to recognize spatially close but distinct idiotopes since they cross-inhibit each other, but elicit anti-anti-id antibodies which inhibit only the binding of the respective immunizing anti-id mAb to mAb CR11-351. mAb T8-203 is the only anti-id mAb which recognizes an idiotope outside the antigen combining site of mAb CR11-351 since it does not inhibit the binding of the latter to target cells and binds to mAb CR11-351 coated B lymphoid cells. In addition, mAb T8-203 defines an idiotope which is shared by seven anti-HLA mAb, while the remaining six anti-id mAb recognize idiotopes which are not detectable on the panel of anti-HLA mAb. mAb T10-352, T10-440 and T10-505 are highly homologous in their VH and VL regions and in their V(D)J junctions suggesting that they may be clonally related. On the other hand, mAb T8-203, T10-649 and T10-938 share some degree of homology in their VH region as all of them use J558 VH genes but differ considerably in their VL regions. Finally, mAb T10-421 is the most unrelated mAb as it utilizes VH, D, JH, VK and JK gene segments different from those of all the other anti-id mAb. These findings indicate that in the HLA-A antigenic system defined by mAb CR11-351 the main mechanism underlying the differential target specificity of syngeneic anti-id mAb is the combinatorial diversity together with the differential pairing of heavy and light chains.
Mol Immunol 1993 Feb
PMID:Serological and molecular characterization of mouse anti-idiotypic monoclonal antibodies elicited with the syngeneic anti-HLA-A2,28 monoclonal antibody CR11-351. 843 7

Prenatal diagnosis of 21-hydroxylase deficiency, the most common cause of congenital adrenal hyperplasia (CAH), has benefited from the advances in endocrinologic and molecular genetic studies. In 1976, prenatal diagnosis of the disease was first attempted by measuring 17-hydroxyprogesterone in the amniotic fluid in the second trimester of pregnancy. Discovery of a close linkage between HLA and the disease gave a second approach for prenatal diagnosis, the latter being made by linkage study of the haplotypes of the index case in a given family. Diagnosis was later made directly by molecular biology. Currently, the studies of the C4-CYP21B gene locus by Southern blotting and the CYP21B gene mutations by PCR methods simplify the diagnostic procedure of an early and accurate prenatal diagnosis in the first trimester. In these conditions all families are now informative. Moreover, using a direct genetic analysis associated with the possibility of detecting the heterozygotes in a non-related CAH population, a prenatal diagnosis can be done in a family without a previously CAH affected child. From our results in a series of 274 pregnancies at risk for CAH in whom prenatal diagnosis has been made by these different approaches, it can be concluded that steroid analysis in the amniotic fluid is an accurate method but provides only a late (second trimester) diagnosis, while an early and accurate diagnosis now relies on adequate molecular genetic studies on chorion villus biopsies. In the aim to prevent the virilization of the external genitalia in CAH female fetuses, prenatal treatment was instituted in our group in 1979 by giving dexamethasone to the mother. This prenatal treatment appears safe for the fetus and the child and is effective in preventing virilization of CAH affected females. Although the degree of prevention is not always complete in all cases, the advantages of prenatal treatment are prevailing over the complications observed in a few mothers.
J Steroid Biochem Mol Biol 1993 Apr
PMID:Prenatal diagnosis and treatment of 21-hydroxylase deficiency. 848 54

Hereditary Hemochromatosis (HFE) is one of the most common inherited disorders with an estimated frequency of homozygous patients of 0.002-0.0045. The disease is characterized by increased intestinal iron absorption and progressive iron overload. Affected subjects show clinical symptoms of parenchymal organ damage after the third-fourth decade of life and have a 200 fold increased risk of developing hepatocellular carcinoma. Early diagnosis and treatment prevent complications and may normalize life expectancy of patients. The biochemical and genetic defects leading to progressive iron accumulation are still unknown, but the HFE gene is tightly linked to HLA complex on the short arm of chromosome 6. Utilizing HLA serotypes and the study of several polymorphic markers of 6p21, a linkage analysis of the disease locus was performed in a series of Italian hemochromatosis families. The data obtained by linkage analysis and the study of a family with a double recombinant allowed us to better define the HFE gene location with respect to HLA-class I A and F loci.
Hum Mol Genet 1993 May
PMID:Linkage analysis of 6p21 polymorphic markers and the hereditary hemochromatosis: localization of the gene centromeric to HLA-F. 851 96


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