Disease relevance of PSMB8

• The aim of this this study was to determine whether polymorphisms of the LMP genes, LMP 2 and LMP 7 are in linkage disequilibrium with Graves' disease [1].
• In many cases, such as in renal cell carcinoma (RCC), the lack of MHC class I antigen presentation can be attributed to the down-regulation of genes needed for antigen processing, such as the transporters associated with antigen processing (TAP)1 and TAP2, and the proteasomal components low molecular weight proteins (LMP)2 and LMP7 [2].
• LMP2 was less frequently expressed than LMP7 in primary and metastatic melanoma lesions [3].
• Lmp2 and Lmp7 were selectively down-regulated in germinal center cell-derived Burkitt's lymphoma (BL) and Hodgkin's lymphoma (HD) cell lines [4].
• In contrast, primary RCC and metastases showed a high frequency of a total lack of heterogeneous TAP1, LMP2 and LMP7 expression, which was often coordinately regulated [5].

Psychiatry related information on PSMB8

• The Y2 receptor has been demonstrated to be the most predominant receptor subtype in the human brain and appears to be involved in many neuropeptide Y actions, such as the regulation of locomotor activity, cardiovascular functions, memory processing, circadian rhythms and release of other neurotransmitters [6].

High impact information on PSMB8

• A subset of the proteasome beta-subunits (LMP2, LMP7, and MECL-1) and one of the accessory complexes, PA28, are upregulated by gamma-interferon and affect the generation of peptides to promote more efficient antigen recognition [7].
• Two beta-subunits of the proteasome, LMP2 and LMP7, are inducible by interferon-gamma and alter the catalytic activities of this particle, enhancing the presentation of at least some antigens [8].
• These results therefore dispute the hypothetical involvement of proteasomes in antigen processing, although a more subtle effect of LMP2 and LMP7 cannot be ruled out [9].
• Transfection experiments showed that the substitution of beta5i (LMP7) for beta5 is necessary and sufficient for producing the peptide, whereas a mutated form of beta5i (LMP7) lacking the catalytically active site was ineffective [10].
• Interferon (IFN) gamma induces replacements of the proteasomal subunits X and Y by LMP7 and LMP2, respectively, resulting in an alteration of the proteolytic specificity [11].

Chemical compound and disease context of PSMB8

• Presentation of the C-terminal ILKEPVHGV epitope is impaired in ME275 melanoma cells by treatment with lactacystin, and is independent of expression of the IFN-gamma-inducible proteasome beta subunits LMP2 and LMP7 [12].
• Variations in peptide YY and Y2 receptor genes are associated with severe obesity in Pima Indian men [13].
• Neonatal exposure to hyperoxia resulted in development of retinal neovascularization that was prevented in Y2(-1-) -mice, and significantly inhibited in rats treated with the Y2-receptor antisense oligonucleotide [14].

Biological context of PSMB8

• The products of the Lmp2 and Lmp7 genes located in the major histocompatibility complex (MHC) class II region are postulated to form part of the proteasome complex [15].
• Delineation of the subunit composition of human proteasomes using antisera against the major histocompatibility complex-encoded LMP2 and LMP7 subunits [15].
• Cleavage of the E4416-424Y peptide was not affected by treatment of the BL cells with IFN-gamma despite both significant up-regulation of Lmp2 and Lmp7 and reconstitution of chymotrypsin and trypsin-like activities against fluorogenic substrates to LCL-like levels [16].
• Down-regulation of Lmp2 and Lmp7 and decreased chymotrypsin- and trypsin-like activities were also observed in purified proteasomes from a c-myc-transfected subline of the ER/EB2-5 LCL that has adopted a BL-like phenotype [16].
• Upregulation of LMP2, but not LMP7, gene expression showed a close correlation with the changes in antibody reactivities observed upon bacterial invasion [17].

Anatomical context of PSMB8

• Low expression of the IFN-gamma-regulated beta low molecular mass polypeptide (Lmp)2, Lmp7, and MECL-1 was demonstrated in a panel of seven BL lines that express the germinal center cell phenotype of the original tumor [16].
• In contrast, LMP7 and TAP2 genes were expressed in these cell lines [18].
• The results demonstrate that, in normal glands, thyrocytes and pancreatic islet cells express comparable moderate to low levels of LMP2 and LMP7 [19].
• Control of LMP7 expression in human endothelial cells by cytokines regulating cellular and humoral immunity [20].
• The findings indicate that regulation of levels of LMP7 is similar to and may be coupled with that of other molecules required for MHC class I-dependent immunity, and depends primarily on cytokines released by Th(1)helper lymphocytes [20].

Associations of PSMB8 with chemical compounds

• These results suggest that NPY activates three receptor subtypes, a Y2 subtype possibly by a direct action on the smooth muscle cells, as well as a Y4 and a Y5 (or 'Y5-like') subtype which, respectively, release acetylcholine and an unknown neurotransmitter [21].
• Analysis of Lmp7 mRNA and protein in paraformaldehyde-fixed placentas by in situ hybridization and immunohistochemistry revealed that both HLA class I-positive and HLA class I-negative trophoblast cells contain Lmp7 gene products [22].
• Utilizing biotinylated-epoxomicin as a molecular probe, we demonstrate that epoxomicin covalently binds to the LMP7, X, MECL1, and Z catalytic subunits of the proteasome [23].
• Using immunohistochemical and in situ hybridization methodologies the localization of neuropeptide tyrosine (NPY) and two of its receptors, the Y1- and the Y2-receptor (R), has been analysed in various tissues in normal animals and animals subjected to different experimental procedures as well as animals with a genetic and an acquired disease [24].
• These findings demonstrate two main points: 1) LMP7 incorporation into the proteasome is of greater importance for the generation of the influenza A2 Matrix epitope than the presence of the LMP7's catalytic site; and 2) the interplay between cytosolic proteases and stability of target proteins is of importance in optimization of Ag presentation [25].

Physical interactions of PSMB8

• However, pharmacological characterization of NPY binding sites in human hypothalamus membranes revealed predominantly the hY2 subtype [26].

Regulatory relationships of PSMB8

• IL-10 downregulated IFN-gamma-induced increases in LMP7 levels, as did IL-12 [20].
• We typed 285 IDDM patients and 337 HLA-DRB1-DQA1-DQB1 genotypically matched control subjects from an ethnically homogeneous population for both the G/T polymorphism in intron 6 of the LMP7 gene and the Arg-His polymorphism in the LMP2 gene [27].

Other interactions of PSMB8

• 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 [28].
• A family-based association method revealed biased transmission of specific alleles from heterozygous parents to affected offspring for the TAP1 gene, as well as for the closely linked LMP2 and LMP7 genes encoding subunits of the immunoproteasome [29].
• These proteins contain an active site of proteolysis, and LMP7 replaces PSMB5 as a component of the 20S proteasome after stimulation of cells by interferon-gamma [30].
• Two major mechanisms in colorectal cancer appear to be responsible for the total loss of MHC surface expression (beta2m mutations and LMP7/TAP2 downregulation) that may contribute to the failure of T lymphocyte recognition during an immune response [31].
• In this tissue, mRNA of Y2 and Y4 NPY receptor subtypes were highly expressed, whereas Y5 mRNA levels were very low and Y1 mRNA levels were intermediate [21].

Analytical, diagnostic and therapeutic context of PSMB8

• RESULTS: In the case control study, no difference in allele or genotype frequency was seen between patients and control subjects at the LMP7 locus [1].
• Western blot analysis of anti-proteasome precipitates demonstrated that the LMP7 protein is incorporated into the proteasome but has a molecular mass of 23 kDa, 7 kDa smaller than expected fro the derived protein sequence of either of the cDNA [32].
• Immunoprecipitation of proteasomes and analysis on two-dimensional gels revealed that during maturation the inducible proteasome subunits LMP2, LMP7, and MECL-1 are up-regulated and that the neosynthesis of proteasomes is switched exclusively to the production of immunoproteasomes containing these subunits [33].
• Consistent with these results, northern blot hybridization studies showed that HLA class I-positive (JEG-3) and HLA null (Jar) trophoblast-derived cell lines contain Lmp7 mRNA [22].
• The relative expression of six proteosome subunits (existing subunits X, Y, and Z and immunoproteosome subunits LMP7, LMP2, and MECL1) in 54 RCCs was investigated using RT-PCR analysis and was compared with clinicopathological measures, including patient outcome [34].

References