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Query: UNIPROT:P06889 (Mol)
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Sex hormones have an effect on various immune responses but the mechanisms of action are unknown. One of these mechanisms might be a modification of expression of major histocompatibility complex (MHC) antigens in blood leucocytes. Estradiol-induced variations of the expression of guinea pig blood leukocytes MHC antigens (GPL-A) was studied. Class I and class II MHC antigens were detected by a sensitive rosetting method using specific alloimmune sera (AIS) and staphylococcal protein A-coated sheep red blood cells (SPA-SRBC) and evaluated by counting the number of bound SPA-SRBC per 100 cells. MHC antigens decreased after estrogen treatment. Estradiol modifies the expression of GPL-A antigens on the mononuclear cells including the Kurloff cells, which are involved in immunity or in a natural killer effect, but did not affect the expression of polymorphonuclear cells, ones which are not involved in immunity.
J Steroid Biochem Mol Biol 1991 Jun
PMID:17 beta estradiol affects the expression of guinea pig blood leukocyte MHC antigens. 206 84

A novel regulatory element which contributes to the regulation of quantitative, tissue-specific differences in gene expression has been found between -771 and -676 bp upstream of the major histocompatibility complex (MHC) class I gene, PD1. Molecular dissection of this element reveals the presence of two overlapping functional activities: an enhancer and a silencer. Distinct nuclear factors bind to the overlapping enhancer and silencer DNA sequence elements within the regulatory domain. The levels of factors binding the silencer DNA sequence in different cell types are inversely related to levels of class I expression; in contrast, factors binding the enhancer DNA sequence can be detected in all cells. In cultured cell lines, inhibition of protein synthesis leads to the rapid loss of silencer complexes, with a concomitant increase in both enhancer complexes and MHC class I RNA. From these data, we conclude that a labile silencer factor competes with a constitutively expressed, stable enhancer factor for overlapping DNA-binding sites; the relative abundance of the silencer factor contributes to establishing steady-state levels of MHC class I gene expression.
Mol Cell Biol 1991 Aug
PMID:A complex regulatory DNA element associated with a major histocompatibility complex class I gene consists of both a silencer and an enhancer. 207 15

Expression of a mammalian major histocompatibility complex (MHC) class I gene is in part regulated by a silencer DNA sequence element which binds a complex of silencer factors. This negative regulatory system is shown to be strikingly similar to the yeast alpha 2 mating-type repression system. A moderate DNA sequence homology exists between the MHC class I silencer DNA element and the yeast alpha 2 operator. Mammalian silencer factors specifically bind to the yeast alpha 2 operator DNA and also specifically interact with a yeast alpha 2-binding protein. Furthermore, the alpha 2 operator functions as a silencer element in mammalian cells when placed upstream of a MHC class I promoter.
Mol Cell Biol 1991 Aug
PMID:Striking similarities between the regulatory mechanisms governing yeast mating-type genes and mammalian major histocompatibility complex genes. 207 16

A cDNA from a B-cell library was previously isolated that encodes a sequence-specific DNA-binding protein with affinities for related sites in a class I major histocompatibility complex (MHC) and kappa immunoglobulin gene enhancers. We report here approximately 6.5 kilobases of sequence of the MBP-1 (MHC enhancer binding protein 1) cDNA. MBP-1 protein has a molecular weight predicted to be greater than 200,000. A DNA-binding domain with high affinity for the MHC enhancer sequence TGGGGATTCCCCA was localized to an 118-amino-acid protein fragment containing two zinc fingers of the class Cys2-X12-His2. Analysis of expression of MBP-1 mRNA revealed relatively high expression in HeLa cells and in a human retinal cell line, with lower levels in Jurkat T cells and in two B-cell lines. Interestingly, expression of MBP-1 mRNA was inducible by mitogen and phorbol ester treatment of Jurkat T cells and by serum treatment of confluent serum-deprived human fibroblasts.
Mol Cell Biol 1990 Apr
PMID:A large protein containing zinc finger domains binds to related sequence elements in the enhancers of the class I major histocompatibility complex and kappa immunoglobulin genes. 210 16

The invariant chain (Ii) is a glycoprotein coexpressed with the major histocompatibility complex (MHC) class II antigens. Although Ii is encoded by a single gene unlinked to the MHC gene complex, Ii and MHC class II appear to have similar patterns of tissue specific expression and generally are coordinately regulated by cytokines. Here we present evidence that transcription of the murine Ii gene is controlled by multiple cis-acting elements. The 5' regulatory region of the Ii gene appears to be combined of conserved class II regulatory elements with promoter elements commonly found in other eucaryotic genes. A region containing characteristic class II promoter elements (H box, X box, and a modified Y box) serves as an upstream enhancer in the Ii gene and might contribute to the coexpression of MHC class II and Ii genes. A series of positive control elements, the kappa B element, Sp1-binding site, and CCAAT box, are present in the Ii promoter and apparently serve distinct regulatory functions. The kappa B site in the Ii gene is a cell type-specific element, contributing to expression in a B-cell line but not in a fibroblast cell line, and the Sp1 site is required by the H-X-Y' enhancer element to stimulate promoter activity. In addition, an Ii enhancer in the first intron that specifically stimulates its own promoter has been identified. Our results suggest that a sequence match between enhancers and certain promoter elements is critical.
Mol Cell Biol 1990 Aug
PMID:Transcriptional control of the invariant chain gene involves promoter and enhancer elements common to and distinct from major histocompatibility complex class II genes. 211 16

Expression of the major histocompatibility complex (MHC) class I and class II antigens and the class II-associated invariant chain (Ii) is strongly increased by treatment of cells with tumor necrosis factor alpha (TNF-alpha) and gamma interferon. We investigated elevation of expression of the invariant chain gene by TNF-alpha. Rat fibroblast cells transfected with the mouse Ii gene containing 802 base pairs of 5' sequences could be stimulated for Ii expression by treatment with TNF-alpha. Analysis of 5'-deleted Ii gene promoter-CAT constructs provided evidence for the presence of a TNF-alpha response box (TRB). Cloning of TRB in front of a non-TNF-alpha-responsive promoter could transfer the TNF-alpha stimulatory effect. We demonstrate binding of a TNF-alpha-induced factor to a kappa B-like motif within TRB. Mutations introduced into the kappa B element of the Ii promoter-CAT plasmid abolished the TNF-alpha-mediated stimulatory effect. Comparison of the TNF-alpha-induced factor and lipopolysaccharide-induced NF-kappa B in gel mobility shift assays upon partial protease digestion suggests similar DNA-binding protein cores. Further support for the NF-kappa B-like nature of the TNF-alpha-induced factor was obtained in methylation interference assays. The TNF-alpha-induced nuclear factor comprises DNA contact sites that are identical to those described for NF-kappa B. This TNF-alpha-induced factor also interacts with kappa B-like sequences of the MHC Kb, Ek alpha, and beta 2-microglobulin promoter, suggesting a common TNF-alpha-mediated regulatory signal for expression of MHC antigens and Ii.
Mol Cell Biol 1990 Aug
PMID:Tumor necrosis factor alpha regulates expression of the major histocompatibility complex class II-associated invariant chain by binding of an NF-kappa B-like factor to a promoter element. 211 19

The major histocompatibility complex (MHC) class II molecule consists of noncovalently associated alpha and beta chains. In mammals studied so far, the class II MHC can be divided into a number of regions, each containing one or more alpha-chain genes (A genes) and beta-chain genes (B genes), and it has been known for some time that orthologous relationships exist between genes in corresponding regions from different mammalian species. A phylogenetic analysis of DNA sequences of class II A and B genes confirmed these relationships; but no such orthologous relationship was observed between the B genes of mammals and those of birds. Thus, the class II regions have diverged since the separation of birds and mammals (approximately 300 Mya) but before the radiation of the placental mammalian orders (60-80 Mya). Comparison of the phylogenetic trees for A and B genes revealed an unexpected characteristic of DP-region genes: DPB genes are most closely related to DQB genes, whereas DPA chain genes are most closely related to DRA-chain genes. Thus, the DP region seems to have originated through a recombinational event which brought together a DQB gene and a DRA gene (perhaps approximately 120 Mya). The 5' untranslated region of all class II genes includes sequences which are believed to be important in regulating class II gene expression but which are not conserved in known pseudogenes. These sequences are conserved to an extraordinary degree in the human DQB1 gene and its mouse homologue A beta 1, suggesting that regulation of expression of this locus may play a key role in expression of the entire class II MHC.
Mol Biol Evol 1990 Nov
PMID:Evolutionary relationships of class II major-histocompatibility-complex genes in mammals. 212 90

Proto-oncogene products c-Fos and c-Jun form a complex which binds with high affinity to the 12-O-tetradecanoylphorbol-13-acetate (TPA) response DNA element and which stimulates transcription of phorbol ester- inducible genes. We have previously identified, by screening a lambda gt11 expression library, murine protein mXBP, which binds to a sequence which overlaps the 3' end of the murine class II major histocompatibility complex A alpha gene X box, a conserved transcription element found upstream of all class II genes. Here, we demonstrate that the target sequence for mXBP is a consensus cyclic AMP response element (CRE). mXBP is a member of the leucine zipper family of DNA-binding proteins and has significant homology to oncoproteins c-Fos and c-Jun. The inferred amino acid sequence of mXBP shows near identity to human CRE-BP1, except it does not contain an internal proline-rich domain. Immunoprecipitation and glutaraldehyde cross-linking studies show that mXBP/CRE-BP2 can form a complex with c-Jun. Complex formation is dependent on intact leucine zipper domains in both proteins. mXBP-c-Jun complexes can coexist with c-Fos-c-Jun complexes and can bind with high affinity to CRE, but not to TPA response DNA element, sequences. These results suggest that changes in the expression of mXBP/CRE-BP2, c-Fos, and c-Jun, which alter the ratio of mXBP-c-Jun to c-Fos-c-Jun complexes, would affect the relative expression of cyclic AMP and phorbol ester-responsive genes. This provides support for a combinatorial model of gene regulation, whereby protein-protein interactions which alter the DNA binding specificity of protein complexes can expand the flexibility of cellular transcriptional responses.
Mol Cell Biol 1990 Apr
PMID:mXBP/CRE-BP2 and c-Jun form a complex which binds to the cyclic AMP, but not to the 12-O-tetradecanoylphorbol-13-acetate, response element. 213 7

Neuroblastomas often show amplification and high expression of the N-myc oncogene. N-myc expression could be explained as a consequence of gene amplification, but an alternative possibility is that expression primarily results from the inactivation or loss of some factor that normally represses the N-myc gene. To test this idea, we fused N-myc-overexpressing neuroblastoma cell lines with lines that do not express N-myc. In the resulting hybrids, N-myc expression turned out to be switched off, although amplified N-myc copies were still present. This suggests that N-myc overexpression in neuroblastomas results, at least in part, from the inactivation of a suppressor gene that is present in normal cells. In rat neuroblastomas, it has been found that N-myc can switch off class I major histocompatibility complex (MHC) expression. Therefore, we analyzed in our hybrid cells whether suppression of N-myc results in reexpression of human class I MHC genes. Because this was found to be the case, the picture emerges of a hierarchic pathway that connects a putative tumor-suppressor gene with the expression of N-myc and consequently of class I MHC, thus affecting the potential immunogenic properties of neuroblastomas.
Mol Cell Biol 1990 Oct
PMID:N-myc expression switched off and class I human leukocyte antigen expression switched on after somatic cell fusion of neuroblastoma cells. 220 14

Evidence from epidemiological and histopathologic studies in humans with autoimmune type 1 (insulin-dependent) diabetes suggests that beta-cell destruction within the islets of Langerhans progresses through a number of stages. In this review we draw on recent experimental evidence in an attempt to define the molecular pathology of these stages. Stage 1 is postulated to be initiated by modification of the beta cell by virus, chemical or other factors, leading to the production of interferon-alpha, hyperexpression of major histocompatibility complex (MHC) class I molecules and induction of MHC class II molecules. Experiments in transgenic mice suggest that overexpression of MHC molecules is in itself detrimental to beta-cell function. Shedding of antigen(s) from dying beta cells in combination with hyperexpression of MHC molecules may be a powerful immunogenic stimulus. Stage 2 commences with infiltration of the islets by immuno-inflammatory cells (termed insulitis). It is proposed that production of cytokines from the infiltrating cells induces "phenotypic switching" in beta cells, with further upregulation of MHC molecules and the induction of intracellular adhesion molecule-1 expression and interleukin-6 production. Together, these properties are seen as a prerequisite for the presentation of autoantigen by beta cells to adherent T lymphocytes and autoimmune activation. The final stage encompasses autoimmune-mediated destruction of the beta cells by the targeted delivery of cytotoxic cytokines and other mediators.
Mol Biol Med 1990 Aug
PMID:Molecular pathology of type 1 diabetes. 223 44


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