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)

The T cell arm of the immune system of higher vertebrates is specific for antigenic peptides bound to cell surface major histocompatibility complex (MHC) molecules. These peptides are derived from two distinct pathways of antigen processing. The class I, or endogenous pathway, utilizes proteasomes and the ubiquitin system for protein degradation, with subsequent transport of the resulting peptides into the lumen of the endoplasmic reticulum by a specific peptide transporter, called TAP. The expression of distinct proteasome subsets is regulated by the cytokine gamma interferon (IFN-gamma). The class II, or exogenous pathway, utilizes the endosomal and lysosomal pathways for protein degradation, and a number of immune-specific accessory molecules including the class-II associated Invariant chain (Ii) and MHC-encoded HLA-DM (H2-DM in mouse) molecules.
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PMID:The genetics of proteasomes and antigen processing. 882 92

HLA class I molecules present antigenic peptides to cytotoxic T lymphocytes and thus play an important role in immune surveillance of cells infected with virus or altered by malignant transformation. Immunochemical studies have demonstrated a marked deficiency or lack of expression of class I molecules on the surface of many different types of tumor cells. It is likely that this allows these cells to escape immune surveillance. In the present study, we examined the molecular basis for lack of expression of class I antigens in small-cell lung carcinoma cell lines. Our results demonstrate that these cell lines also lacked products of MHC-encoded proteasome subunit LMP2 and the putative peptide transporter TAP1. In contrast, LMP7 and TAP2 genes were expressed in these cell lines. Pulse-chase experiments showed that class I molecules were unstable and thus not transported to the cell surface from endoplasmic reticulum. Our results suggest that antigenic peptides were not available for binding to class I alpha chains due to lack of TAP1 and LMP2 gene products. Investigations of the regulatory mechanisms of TAP1 and LMP2 genes showed that the tumor cells lacked trans -regulatory nuclear protein(s), which binds to the interferon-gamma (IFN-gamma) response element (ISRE) in the TAP1, LMP2 bidirectional intergenic promoter. Treatment of tumor cells with IFN-gamma induced ISRE-binding nuclear protein(s) and resulted in expression of TAP1 and LMP2 genes with a concomitant increase in cell-surface expression of class I molecules. Our data provide credence for a role of TAP and LMP genes in immune response.
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PMID:Molecular basis for lack of expression of HLA class I antigens in human small-cell lung carcinoma cell lines. 893 46

In primary embryonal fibroblasts from transgenic mice expressing H-2 genes and a miniature swine class I transgene (PD1), transformation with the highly oncogenic Ad12 results in a reduction in peptide transporter and proteasome-associated (LMP2 and LMP7) gene expression, and suppression in transport and cell surface expression of all class I antigens. The selective suppression in transport of H-2 (but not of PD1) molecules in cells reconstituted for the expression of peptide transporter and LMP genes implied that an additional factor(s) is involved in the assembly of class I complexes. Here we show that the beta2m, H-2Db, and H-2Kb genes are transcribed and translated in Ad12-transformed cells. However, unlike normal and E1Ad5-transformed cells, in which beta2m is either secreted unbound or bound to class I heavy chains, in Ad12-transformed cells significant amounts of beta2m are retained in the cell bound to the membrane, but free of class I heavy chains. This abnormal turnover of beta2m in the Ad12-transformed cells suggests the existence of a novel beta2m-binding molecule(s) that sequesters beta2m, and this process may provide a mechanism by which transformation with Ad12 may subvert class I complex formation.
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PMID:Synthesis and turnover of beta2-microglobulin in Ad12-transformed cells defective in assembly and transport of class I major histocompatibility complex molecules. 899 69

Cell-mediated immunity is effective against cells harboring active virus replication and is critical for the elimination of ongoing infections, opposing tumor progression, and reducing or preventing the reactivation of persistent viruses and tumor metastasis. The capacity of persistent viruses and tumor cells to maintain a long-term relationship with their host presupposes mechanisms for circumventing antiviral or antitumor defenses. By suppressing the expression of molecules associated with antigen processing and presentation, abrogation of the major immune mechanism that deals with the elimination of infected and transformed cells is achieved. This is accomplished in tumors predominantly by transcriptional downregulation of genes encoding class I major histocompatibility complex antigens, peptide transporter molecules, and the proteasome-associated low molecular mass protease subunits, and in cells expressing viral proteins by interfering with peptide transport and the assembly/transport of class I complexes. In addition, virus-infected cells and selected tumor cells express mainly nonimmunogenic or antagonistic peptide epitopes. This review describes mechanisms used by viruses and in transformed cells for interference with antigen processing and presentation and addresses their significance for in vivo viral persistence and tumor progression.
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PMID:Modulation of antigen processing and presentation by persistent virus infections and in tumors. 929 29

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

Protein degradation by the ubiquitin system controls the intracellular concentrations of many regulatory proteins. A protein substrate of the ubiquitin system is conjugated to ubiquitin through the action of three enzymes, E1, E2 and E3, with the degradation signal (degron) of the substrate recognized by E3 (refs 1-3). The resulting multi-ubiquitylated substrate is degraded by the 26S proteasome. Here we describe the physiological regulation of a ubiquitin-dependent pathway through allosteric modulation of its E3 activity by small compounds. Ubr1, the E3 enzyme of the N-end rule pathway (a ubiquitin-dependent proteolytic system) in Saccharomyces cerevisiae mediates the degradation of Cup9, a transcriptional repressor of the peptide transporter Ptr2 (ref. 5). Ubr1 also targets proteins that have destabilizing amino-terminal residues. We show that the degradation of Cup9 is allosterically activated by dipeptides with destabilizing N-terminal residues. In the resulting positive feedback circuit, imported dipeptides bind to Ubr1 and accelerate the Ubr1-dependent degradation of Cup9, thereby de-repressing the expression of Ptr2 and increasing the cell's capacity to import peptides. These findings identify the physiological rationale for the targeting of Cup9 by Ubr1, and indicate that small compounds may regulate other ubiquitin-dependent pathways.
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PMID:Peptides accelerate their uptake by activating a ubiquitin-dependent proteolytic pathway. 1085 Jul 18

An association between oncogenic transformation and repression of different components of the MHC class I antigen processing machinery (APM) have been described in murine model systems. In order to discover whether a similar correlation exists, human tumor cell lines of distinct histology with altered ras protein were analyzed for the expression of APM components utilizing RT-PCR and Western blot analyses. A heterogeneous expression pattern of MHC class I antigens, TAP peptide transporter, proteasome subunits, proteasome activator PA28 and the chaperones calnexin, calreticulin as well as tapasin was displayed by these tumor cell lines. Single or combined deficiencies in the expression and/or function of TAP, LMP2, LMP10 and tapasin were demonstrated in 11 of 12 cell lines studied, whereas the expression of calnexin, calreticulin, beta2-microglobulin, LMP7 and PA28alpha was unaltered or only weakly decreased. The impaired expression of TAP, LMP subunits and tapasin was not associated with altered ras, but resulted in reduced MHC class I surface expression. In particular, a significant allele- and locus-specific downregulation of the HLA-A and HLA-B haplotypes was found. IFN-gamma treatment corrected the TAP, LMP and tapasin deficiencies and enhanced the constitutive PA28alpha, LMP7, calnexin and calreticulin expression which was accompanied with increased levels of MHC class I antigens. Thus, dysregulation rather than structural alterations of different APM components might be one mechanism of colon carcinoma, small cell lung carcinoma and pancreatic carcinoma cell lines to evade immune recognition.
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PMID:Functional deficiencies of components of the MHC class I antigen pathway in human tumors of epithelial origin. 1093 98

In murine tumor cell lines, downregulation of MHC class I surface expression has been frequently detected, but the underlying molecular mechanisms of such deficiencies have not been defined. In this study, murine tumor cell lines of different histology derived from spontaneous or from chemical-induced tumors were analyzed for the expression of multiple components of the major histocompatibility complex (MHC) class I antigen-processing machinery (APM), including the peptide transporter TAP, the interferon (IFN)-gamma inducible proteasome subunits and several chaperones. The tumor cell lines analyzed demonstrated a heterogeneous expression pattern of various APM components. In comparison to control cells an impaired coordinated expression of at least three APM components was detected. In particular, extensive APM deficiencies were found in cell lines derived from chemical-induced tumors. A strong coordinated downregulation of expression and/or function of TAP, the low molecular weight proteins (LMP) subunits, the proteasome activator PA28 and/or tapasin was found in 5 of 10 tumor cells, which was associated with impaired MHC class I surface expression. In contrast, the expression of beta2-microglobulin (beta2-m), PA28beta, the constitutive proteasome subunits X, Y, Z and of the chaperones calnexin, calreticulin, ER60 and phospho disulfide isomerase (PDI) was unaltered or only weakly decreased. The deficient expression of APM components could be corrected by IFN-gamma treatment, which also reconstituted MHC class I surface expression. However, impaired expression of APM molecules appears not to be the only cause of abnormal MHC class I expression, since it could neither be corrected by the addition of exogeneous MHC class I binding peptides nor by incubation at low temperature. These results suggest that one major mechanism of murine tumor cells, in particular chemical-induced tumors, to evade the immune system is the combined dysregulation of various APM components and other factors, which still have to be identified.
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PMID:Coordinate downregulation of multiple MHC class I antigen processing genes in chemical-induced murine tumor cell lines of distinct origin. 1109 32

Human tumor cells frequently exhibit abnormalities in the major histocompatibility complex (MHC) class I surface expression which can be due to structural alterations and/or dysregulation of various components of the MHC class I antigen processing machinery, such as HLA class I heavy and light chains, the peptide transporter and the proteasome subunits. Although several cofactors critical for proper MHC class I assembly have been identified, their contribution to the immune escape phenotype of tumor cells has not been analyzed. In order to determine whether tapasin deficits are an integral part of immune escape mechanisms of human tumors, we studied the constitutive and cytokine-regulated expression pattern of tapasin in malignant cells of distinct histology. Heterogeneous and reduced expression levels of tapasin were found in small-cell lung carcinoma, pancreatic carcinoma, colon carcinoma, head an neck squamous cell carcinoma and renal cell carcinoma cell lines. Tapasin downregulation was also prominent in surgically removed tumor lesions when compared to normal controls. The impaired tapasin expression is often associated with low MHC class I cell surface expression. In addition, various cytokines, including interferon (IFN)-alpha, IFN-gamma, tumor necrosis factor (TNF)-alpha and interleukin (IL)-4, but not granulocyte-macrophage colony stimulating factor (GM-CSF), transcriptionally upregulate to a distinct extent and in a time-dependent manner tapasin expression in tumor cells. Thus, deficient tapasin expression appears to be a frequent event in human tumor cells. Its restoration by cytokines further suggests that impaired tapasin expression in tumors is rather due to dysregulation than to structural alterations.
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PMID:Downregulation of the constitutive tapasin expression in human tumor cells of distinct origin and its transcriptional upregulation by cytokines. 1116 57

The murine B16 melanoma system represents an important in vivo model for the evaluation of T cell-based immunization and vaccination strategies, although deficient MHC class I surface expression has been identified in these cells. We postulate here that the MHC class I-deficient phenotype of B16 melanoma cells is attributable to down-regulation or the loss of the expression and function of multiple components of the MHC class I antigen-processing pathway, including the peptide transporter associated with antigen processing, the proteasome subunits LMP2, LMP7, and LMP10, PA28alpha and -beta, and the chaperone tapasin. In contrast, calnexin, calreticulin, ER60, and protein disulfide isomerase expression are unaltered or only marginally suppressed in these cells. The level of down-regulation of the components of the antigen-processing pathway is either transcriptionally or posttranscriptionally controlled and could be corrected in all cases by IFN-y treatment, which also reconstituted MHC class I surface expression. Thus, B16 melanoma cells can be used as a model for the characterization of the mechanisms underlying the coordinated dysregulation of the antigen-processing components, which should provide new insights into the development of tumors and the factors controlling this process.
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PMID:Characterization of the major histocompatibility complex class I deficiencies in B16 melanoma cells. 1122 38


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