Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.25.1 (proteasome)
28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Major histocompatibility complex (MHC) class I molecules associate with peptides derived from endogenously synthesized antigens. Cytotoxic T-lymphocytes can thus scan class I molecules and bound peptide on the surface of cells for foreign antigenic determinants. Recent evidence demonstrates that the products of trans-acting, non-class I genes in the class II region of the MHC are required in the class I antigen-processing pathway. There are genes (called HAM1 and HAM2 in the mouse) in this region that encode proteins postulated to be involved in the transport of peptide fragments into the endoplasmic reticulum for association with newly synthesized class I molecules. But, the mechanism by which such peptide fragments are produced remains a mystery. At least two genes encoding subunits of the low-molecular mass polypeptide (LMP) complex are tightly linked to the HAM1 and HAM2 genes. We show that the LMP complex is closely related to the proteasome (multicatalytic proteinase complex), an intracellular protein complex that has multiple proteolytic activities. We speculate that the LMP complex may have a role in MHC class I antigen processing, and therefore that the MHC contains a cluster of genes required for distinct functions in the antigen processing pathway.
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PMID:Structural and serological similarity of MHC-linked LMP and proteasome (multicatalytic proteinase) complexes. 192 32

Four genes, closely linked to major histocompatibility complex (MHC) class II genes, have been identified in humans, mice, and rats and are thought to be involved in the generation and transport of endogenous immunogenic peptides for the MHC class I antigen-processing pathway. The Tap-1 and Tap-2 genes presumably encode a heterodimeric protein complex responsible for transporting endogenous immunogenic peptides to the lumen of the endoplasmic reticulum. The Lmp-2 and Lmp-7 gene products are two subunits of the large cytosolic proteasome complex possibly involved in generation of endogenous peptides. To study the genetic polymorphism of the Lmp-2 gene, we used a published cDNA sequence as a consensus sequence and PCR-amplified, cloned, and sequenced the Lmp-2 gene from 12 inbred mouse strains. We found three amino acid variants, LMP-2d, LMP-2b, and LMP-2q, which partially correlated with restriction fragment length polymorphism variants identified with Southern blots. Allelic polymorphism of the Lmp-2 gene may be involved in peptide selection, leading to autoimmune disease susceptibility.
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PMID:Molecular basis of genetic polymorphism in major histocompatibility complex-linked proteasome gene (Lmp-2). 768 85

The non-essential mouse proteasome beta-type subunits LMP2 and LMP7 are thought to connect proteasomes to the MHC class I antigen processing pathway. Both subunits are synthesized as proproteins. We have studied the processing of both subunits, correlated with the maturation of 20 S proteasomes in mouse T cells. Our data show that proteasome assembly occurs via 13-16 S precursor complexes which possess a protein pattern distinct from that of 20 S proteasomes. Both LMP2 and LMP7 proproteins are processed within these preproteasome complexes and only their processed forms become part of active 20 S proteasomes. Our data show that the maturation and assembly of 20 S proteasomes via precursor particles is a translation-dependent gradual process, that processing of subunit proproteins takes place in these 13-16 S complexes and that subunit processing and proteasome formation occur together.
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PMID:20 S proteasomes are assembled via distinct precursor complexes. Processing of LMP2 and LMP7 proproteins takes place in 13-16 S preproteasome complexes. 812 Sep 5

The mouse pancreatic beta TC3 and beta TC6-F7 cell lines were used to characterize the effects of interferon-gamma (IFN-y) on beta-cell phenotype and function. Initially, intracellular and secreted insulin were compared in glucose-stimulated cells over time. A significant reduction in insulin content and secretion was observed on a per-cell basis in glucose-stimulated beta TC3 and beta TC6-F7 cells after 12 h of exposure to IFN-gamma. The steadystate level of pre-proinsulin mRNA expression was not affected by IFN-gamma. Thus, we postulate that IFN-gamma's inhibitory actions occur after transcription of pre-proinsulin genes. Time-course analysis of IFN-gamma-regulated mRNA expression of the two intra-MHC-encoded subunits of the proteasome (low-molecular-mass polypeptide [Lmp]-2 and Lmp-7) revealed a correlation between their induction and the inhibitory effects of IFN-gamma on glucose-stimulated insulin production. Increased expression of Lmp-2 and Lmp-7 mRNA was accompanied by a corresponding induction of LMP2 and LMP7 protein expression. Subsequently, major histocompatibility complex (MHC) class I cell-surface expression was significantly increased in IFN-gamma-treated beta TC3 and beta TC6-F7 cells. Exposure of IFN-gamma-treated beta-cells to a peptide aldehyde inhibitor of the proteasome (MG132) significantly attenuated MHC class I cell-surface expression but did not prevent the negative effects of IFN-gamma on glucose responsiveness. Enhanced expression of the MHC class I antigen processing and presentation pathway and diminished insulin production appear to be distinct pathological alterations in beta-cells exposed to the insulitic cytokine IFN-gamma.
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PMID:Interferon-gamma independently activates the MHC class I antigen processing pathway and diminishes glucose responsiveness in pancreatic beta-cell lines. 913 43

Malignant transformation is often associated with genetic alterations providing tumor cells with mechanisms for escape from immune surveillance. Human and murine tumors of various origin as well as in vitro models of viral and oncogenic transformation express reduced levels of major histocompatibility complex (MHC) class I antigens resulting in decreased sensitivity to MHC class I-restricted cytotoxic T lymphocyte (CTL)-mediated lysis. We here investigate whether the suppressed MHC class I surface expression of ras-transformed fibroblasts is due to dysregulation of the genes of the antigen-processing machinery, the peptide transporters TAP-1 and TAP-2 and the proteasome subunits LMP-2 and LMP-7, and whether it can be restored by gene transfer. In comparison to parental NIH3T3 cells, the ras oncogenic transformants revealed reduced TAP and LMP mRNA expression and impaired function of these genes, leading to deficient peptide transport and peptide loading of MHC class I molecules resulting in instable expression of the MHC class I complex on the cell surface. Enhanced H-2 surface expression due to stabilization of the MHC class I complex could be achieved by culturing ras transformants at low, unphysiological temperature (26 degrees C) or by loading these cells with either exogenous human beta2-microglobulin or MHC class I-binding peptide alone or in combination. Furthermore, interferon-gamma treatment was capable to enhance the expression of TAP, LMP and MHC class I molecules in both parental as well as ras-transformed fibroblasts. Stable transfection of the human TAP-1 cDNA into ras transformants caused a partial reconstitution of the peptide transport and an enhancement of the MHC class I surface expression, whereas the level of MHC class I biosynthesis was not affected by TAP-1 overexpression in parental cells. Together these results point to the existence of an association between oncogenic transformation and deficiencies in the MHC class I antigen-restricted immunosurveillance, suggesting intervention strategies involving specific MHC class I-binding peptides or transfection of the LMP and/or TAP genes to overcome the expression of the immune escape phenotype.
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PMID:Down-regulation of the MHC class I antigen-processing machinery after oncogenic transformation of murine fibroblasts. 948 92

Some human tumor cells exhibit deficient expression of the peptide transporters TAP1 and TAP2 and of the proteasome subunits low molecular weight protein (LMP)-2 and LMP-7, which could be partially restored by cytokine treatment. Here, we show that IFN-gamma stimulation of human renal cell carcinoma lines increased the MHC class I, transporter associated with antigen processing (TAP), and LMP transcript and protein levels, but TAP and LMP expression are more rapidly induced by IFN-gamma than MHC class I molecules. No correlation between the level of induction of the MHC class I antigen presentation genes and IFN sensitivity/resistance was detected. The IFN-gamma-mediated increase of MHC class I, TAP-1, and LMP-2 expression was independent of de novo protein synthesis. Analysis of the dual TAP-1/LMP-2 promoter activity revealed that TAP-1 and LMP-2 expression are controlled by IFN-gamma at the transcriptional level. Site-specific mutations in the IFN-gamma-responsive element of the TAP-1/LMP-2 promoter blocked induction by IFN-gamma. Thus, the IFN-gamma-mediated coordinated transcriptional up-regulation of TAP-1 and LMP-2 expression occurs through the use of a common regulatory element, which might result in enhanced recognition of renal cell carcinoma cells by the immune system.
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PMID:IFN-gamma-mediated coordinated transcriptional regulation of the human TAP-1 and LMP-2 genes in human renal cell carcinoma. 981 22

Specific CD8(+) CTL recognition of melanoma requires expression of MHC class I molecules as well as melanoma-associated peptide epitopes. Human melanoma cells may escape immune recognition by a variety of means, including global or allelic down-regulation of MHC class I molecules. Stable MHC class I cell surface expression requires delivery of cytosolic peptides into the endoplasmic reticulum by the peptide transporter molecules TAP1 and TAP2, with peptides subsequently transported to the cell surface in complexes containing MHC class I heavy chain and beta2-microglobulin. We have evaluated a series of mechanisms resulting in MHC class I down-regulation in a human melanoma cell line, Mz18, typed as HLA-A2(+), A3(+), B7(+), B57(+), Cw1(+), and Cw6(+) by genomic PCR analysis. The melanoma cell line Mz18 exhibits a global down-regulation of MHC class I heavy chain transcripts; beta2-microglobulin; the proteasome subunits LMP2/7, involved in generating cytosolic peptide fragments; and the peptide transporter molecules TAP1 and TAP2, involved in peptide transport from the cytosol into the endoplasmic reticulum. IFN-gamma treatment of Mz18 melanoma cells leads to up-regulation of LMP2/7 and TAP1/2, as well as to up-regulation of HLA-B and HLA-C MHC loci alleles, but not HLA-A2 or HLA-A3. Karyotypic analysis and fluorescence in situ hybridization with chromosome 6 and MHC class I-specific probes showed complex rearrangement of one chromosome 6 involving the MHC class I locus on 6p and translocation of 6q to the long arm of chromosome 19. To evaluate the capability of melanoma Mz18 to present tumor-specific peptides to HLA-A2-restricted, melanoma-specific CTLs, we restored HLA-A2 surface expression by retroviral-mediated transfer of functional HLA-A2 cDNA. Melanoma peptides could only be presented and recognized by CTLs if the HLA-A2-transfected Mz18 cell line was first treated with IFN-gamma, thereby restoring LMP2/7 and TAP1/2 expression and function. Because several melanoma antigens recognized by T cells have been reported to be presented by HLA-A2 (MART-1/Melan-A, tyrosinase, gp100, and MAGE-3), the loss of HLA-A2 molecules may represent an important mechanism by which many melanomas evade immune recognition. These findings suggest that patients entering clinical trials for immunotherapy with melanoma vaccines should be carefully examined for tumor cell allelic MHC class I loss and whether such MHC class I antigen down-regulation can be restored by cytokines.
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PMID:Tumor escape from immune recognition: loss of HLA-A2 melanoma cell surface expression is associated with a complex rearrangement of the short arm of chromosome 6. 981 14

Suppression of MHC class I expression is thought to allow tumor cells to escape immune surveillance mediated by CD8(+) CTLs. For stable MHC class I surface expression, multiple protein interactions are required for efficient assembly of MHC class I heavy chain and beta 2-microglobulin with endogenous peptides. Peptide processing and transport into the endoplasmic reticulum involves the genes of the transporters associated with antigen processing, TAP-1 and TAP-2, and the two components of the proteasome complex, the low molecular weight proteins LMP-2 and LMP-7. We selected human renal cell carcinoma (RCC) cells derived from a tumor that is thought to be controlled by host immunity to study the MHC class I antigen presentation machinery. Eleven RCC lines established from primary tumors were investigated for the mRNA and protein expression of MHC class I, TAP, and LMP genes. In addition, membrane stability of MHC class I was determined by incubation of the RCC cell lines at low temperature and in the presence of exogenous HLA-binding peptides. Our results revealed the existence of two different phenotypes of RCC cell lines. Group I displayed temperature-stable MHC class I surface expression associated with high, and in most cases coordinated, expression of MHC class I heavy and light chain, TAP and LMP transcripts, and proteins. Group II demonstrated a marked MHC class I instability at 37 degreesC associated with low but coordinated expression of the respective transcripts and proteins. MHC class I membrane expression of group II, but not of group I RCC cells, could be stabilized by incubation with specific MHC class I binding peptides. These results suggest an important role of the genes of the antigen presentation machinery in stable and efficient MHC class I surface expression of RCC cells. However, it has still to be defined whether deficient antigen processing is one of the mechanisms of RCC cells to escape the surveillance of the immune system.
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PMID:Reduced membrane major histocompatibility complex class I density and stability in a subset of human renal cell carcinomas with low TAP and LMP expression. 981 17

The proteasome regulator PA28, which can be upregulated by IFN, is important in the modulation of proteasome activity. Since the proteasome has been implicated in the processing of the major histocompatibility complex (MHC) class I antigens, it was of interest to determine the regulatory elements of PA28 at the genomic level. Although PA28 has been found in different species, the gene layout on the chromosome was not determined. In this study, the genetic organization of mouse PA28b was characterized. Two copies of the PA28b gene, namely b1 and b2, were found by restriction fragment mapping and Southern hybridization. By fluorescence in situ hybridization, the location of the two PA28b genes was determined on chromosomes 11 and 14. PA28b1 has 11 exons, whereas PA28b2 has no introns and appears to be a nonfunctional pseudogene. The 5' promoter region of PA28b1 contains several transcriptional factor binding sites including two IFN responsive elements. The expression levels of PA28 and other gene products involved in MHC class I antigen presentation appear to be correlated in various tissues. Notably, PA28 is expressed at high levels in immunological tissues such as spleen and peripheral blood leukocytes. Taken together, PA28 seems to be co-regulated with other molecules involved in MHC class I antigen presentation.
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PMID:Characterization of the mouse proteasome regulator PA28b gene. 991 29

The generation of antigenic peptides bound and presented to the immune system by MHC class I molecules predominantly depends on the function of the proteasome system. Stimulation of cells with interferon gamma induces the incorporation of three active site bearing beta-subunits into the 20S proteasome and the formation of the PA28 proteasome modulator complex. PA28 alters the cleavage properties of the proteasome and enhances MHC class I antigen presentation. Thus, by cytokine induced change of the proteasome system cells may alter the proteolytic properties of the 20S proteasome and may render an organism more flexible in its peptide generation capacity.
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PMID:The role of the proteasome system and the proteasome activator PA28 complex in the cellular immune response. 1022 31


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