Disease relevance of PSME1

• The REGalpha RTP site is needed to enhance the presentation of a cytomegalovirus pp89 protein-derived epitope by MHC class I molecules in mouse fibroblasts [1].
• Full-length cDNAs for three human proteasome activator subunits, called REGalpha, REGbeta, and REGgamma, have been expressed in Escherichia coli, and the purified recombinant proteins have been characterized [2].
• Protein IGUP I-5111 was selected for further studies as its level is affected by simian-virus-40 transformation and because peptide sequences were available in the microsequence database [3].
• RESULTS: Anti-PA28alpha> antibody was detected in serum from 23% of patients with systemic lupus erythematosus (SLE) and 24% with Sjögren's syndrome (SS) [4].
• Western blotting confirmed that PSME mediated high E1A protein expression in PSMA-positive, androgen-independent prostate cancer cells (C4-2 and CWR22rv), but was much less active in PSMA-negative cancer cells (PC-3 and A549) [5].

High impact information on PSME1

• Whereas REGalpha activates proteasomal hydrolysis of peptides with hydrophobic, acidic or basic residues in the P1 position, REGgamma only activates cleavage after basic residues [6].
• Five REGalpha mutants that remain inactive in the mixing assay contain amino acid substitutions clustered between Arg-141 and Gly-149 [7].
• Combining PCR mutagenesis with an in vitro activity assay, we have isolated and characterized 36 inactive, single-site mutants of recombinant REGalpha [7].
• In contrast to such extreme deficiencies, we found unaltered or only partially decreased expression of PA28alpha and PA28beta in tumor cell lines [8].
• In this study, we describe the complete nucleotide sequences of the mouse genes, Psme1, Psme2, and Psme3, coding for the alpha-, beta-, and gamma-subunits, respectively [9].

Chemical compound and disease context of PSME1

• Furthermore, ionomycin (calcium ionophore) and TPA augmented the enhancer activity of PSME, implying that calcium is an important regulator for PSMA expression in prostate cancer cell [10].
• Homologous genes included an interferon-gamma-induced human gene, (IGUP I-5111), alpha-1 protease inhibitor gene, human retinoblastoma susceptibility gene, and human creatine kinase gene (two clones) [11].

Biological context of PSME1

• Two proteasome activators PA28alpha and beta, which have been implicated in antigen processing for loading class I MHC molecules, are synthesized in response to Ifn-gamma [12].
• Proteasome activity is further changed by the IFN-gamma-mediated induction of the proteasome regulator PA28alpha/beta and the downregulation of PA28gamma [13].
• One mutation in this loop (N146Y) yields a REGalpha heptamer that binds the proteasome as tightly as wild-type REGalpha but does not activate peptide hydrolysis [7].
• Like the wild-type molecule, REGalpha chimeras activated all three proteasome catalytic subunits regardless of the carboxyl-terminal sequence [14].
• Pronounced up-regulation of the PA28alpha/beta proteasome regulator but little increase in the steady-state content of immunoproteasome during dendritic cell maturation [15].

Anatomical context of PSME1

• REG, purified from red blood cells, is a complex of REG alpha and REG beta subunits [16].
• RAPA and FK506 also repressed the up-regulated PA28 alpha messages in phytohemagglutinin (PHA)-stimulated T cells [17].
• PA28 alpha and gamma were detected mainly in the cytosol and to a lesser extent in the crude nuclear pellet, however the purified nuclei were devoid of PA28 alpha and gamma [18].
• OBJECTIVE: To determine the autoimmune response against proteasome activator 28alpha (PA28alpha) in patients with various connective tissue diseases, and to compare the immunoreactivity between anti-PA28alpha and anti-Ki antibodies [4].
• Interferon-gamma up-regulates a unique set of proteins in human keratinocytes. Molecular cloning and expression of the cDNA encoding the RGD-sequence-containing protein IGUP I-5111 [3].

Associations of PSME1 with chemical compounds

• Proteasome activator subunit PA28 alpha and related Ki antigen (PA28 gamma) are absent from the nuclear fraction purified by sucrose gradient centrifugation [18].
• IGUP I-5111 contains the RGD sequence found in many extracellular glycoprotein ligands of the integrin receptor family and it is found at least partially in the culture supernatant [3].
• The Psme1 and Psme2 genes are located approximately 6 kb apart with their 3'-ends pointing toward each other on bands C2 to D1 of mouse chromosome 14, supporting the idea that they emerged by tandem duplication [9].
• PSME-enhanced expression is repressed in the presence of androgen, mimicking the repression of the endogenous FOLH1 gene [19].

Physical interactions of PSME1

• Each subunit is capable of activating the proteasome, and when combined, they form superactive REGalpha/REGbeta complexes [20].

Regulatory relationships of PSME1

• Recombinant alpha and beta subunits bind each other with high affinity, and the REGalpha/beta heteromeric complex activates hydrolysis of LLVY-methylcoumaryl-7-amide (LLVY-MCA) and LLE-beta-nitroanilide (LLE-betaNA) more than REGalpha or REGbeta alone [2].

Other interactions of PSME1

• At the transcript level, the interferon-gamma-responsive subunits LMP2 (beta1i), MECL1 (beta2i), and the proteasome activator subunit PA28alpha were markedly up regulated [21].
• Finally we showed that the human chromosomal genes of PA28 alpha and PA28 gamma were located on 14q11.2 and 17q21.32-21.33, respectively [22].
• Likewise, the expression of the IFN-gamma-inducible proteasome regulator PA28 alpha beta was also impaired in MCMV-infected cells [23].
• Further, HSC5 and HSC7 show diminished expression of LMP7/tapasin, and PA28alpha/beta, respectively [24].
• METHODS: Serum samples were obtained from 219 patients with various connective tissue diseases. cDNA encoding full-length human PA28alpha and Ki were produced by polymerase chain reaction [4].

Analytical, diagnostic and therapeutic context of PSME1

• METHODS: Real time quantitative RT-PCR was used to analyse the mRNA expression pattern of the proteasome activator subunits PA28alpha and PA28beta and of constitutive proteasome and interferon-gamma-inducible immunoproteasome subunits in peripheral blood mononuclear cells [21].
• At the protein level, RAPA inhibited PA28 alpha and PA28 beta in the activated T cells according to immunoblotting and confocal microscopy [17].
• The immunoreactivity of serum for PA28alpha and Ki was studied by Western blotting [4].
• To investigate whether this finding was due to the presence of cross-reacting epitopes for PA28alpha and Ki antigens, an inhibition test was performed by ELISA [4].
• Subsequent site-directed mutagenesis changing the AP-3 site abolished the enhancer activity of PSME but not AP-1, indicating that AP-3 was the key cis-element enabling high PSMA expression [10].

References