Disease relevance of NPEPPS

• Modeling of the pH- and the temperature-dependent deviations of the free to total PSA (prostate specific antigen) ratios for clinical predictability of prostate cancer and benign prostate hyperplasia [1].
• A genomic screen for modifiers of tauopathy identifies puromycin-sensitive aminopeptidase as an inhibitor of tau-induced neurodegeneration [2].
• PSA doubling time predicts the outcome after active surveillance in screening-detected prostate cancer: Results from the European randomized study of screening for prostate cancer, Sweden section [3].
• Prostate adenocarcinomas with a BRAF mutation tended to show higher preoperative serum PSA levels, Gleason scores and tumor stages than prostate adenocarcinomas with a KRAS mutation [4].
• Here we have extended these observations using human recombinant PSA purified from Escherichia coli [5].

High impact information on NPEPPS

• We used a cross species functional genomic approach to analyze gene expression in multiple brain regions in mouse, in parallel with validation in Drosophila, to identify tau modifiers, including the highly conserved protein puromycin-sensitive aminopeptidase (PSA/Npepps) [2].
• Although we observed some proteolytic activity in fractions enriched in endoplasmic reticulum, it could not compensate for the loss of tripeptidyl peptidase II/puromycin-sensitive aminopeptidase activities [6].
• One antigenic peptide, FAPGNYPAL, was rapidly destroyed in the extracts by a bestatin-sensitive exopeptidase, apparently by the puromycin-sensitive aminopeptidase [7].
• Taken together, these data favor the novel idea that PSA participates in proteolytic events essential for cell growth and viability [8].
• Furthermore, puromycin and bestatin both arrested the cell cycle, leading to an accumulation of cells in G2/M phase, and ultimately induced cells to undergo apoptosis at concentrations that inhibit PSA [8].

Chemical compound and disease context of NPEPPS

• OBJECTIVE: To evaluate the PSA response rate to prednisone in asymptomatic patients with hormone refractory prostate cancer (HRPC) [9].

Biological context of NPEPPS

• The human PSA gene is composed of 23 exons and 22 introns and spans approximately 40 kb of chromosome 17 at the interval 17q12-21 [10].
• An analysis of the 5' end of the human PSA transcript reveals that the translational start site corresponds to nt 210 of the human PSA cDNA, as suggested by RT-PCR, 5' RACE, and computer analysis of expressed sequence tags [10].
• The gene (NPEPPS alias PSA) was physically mapped to chromosome 17q21.2-->q21.32 using fluorescence in situ hybridization [11].
• Using proteomics, we identified two cytosolic peptidases, tripeptidyl peptidase II and puromycin-sensitive aminopeptidase, that trimmed the N-terminal extensions of the precursors produced by the proteasome, and led to a transient enrichment of the final antigenic peptide [6].
• Additionally, PSA was able to digest soluble tau purified from normal human brain to a greater extent than either soluble or PHF tau purified from AD brain, indicating that post-translational modifications and/or polymerization of tau may affect its digestion by PSA [5].

Anatomical context of NPEPPS

• Here we report on the analysis of a novel mouse cDNA encoding the puromycin-sensitive aminopeptidase (PSA) and on its expression in COS cells and 3T3 fibroblasts [8].
• Anti-rat brain-soluble PS-Ap IgG detected immunoreactive material in epithelium, glands, and endothelium [12].
• In univariate analysis, Gleason score, preoperative PSA, extraprostatic extension, margin, seminal vesicle invasion, and high COX-2 expression were significant predictors of biochemical recurrence (p < 0.05) [13].
• In contrast, since chronic imipramine treatment is not associated with neurogenesis in the medial prefrontal cortex, increased expression of PSA-NCAM and pCREB in the prelimbic cortex implicates changes in synaptic connectivity in this brain region [14].
• Since PSA-NCAM and pCREB are expressed in recently-generated neurons in the dentate gyrus, it is likely that chronic imipramine treatment increased their expression in the hippocampus at least partially by increasing neurogenesis [14].

Associations of NPEPPS with chemical compounds

• An analysis of Alzheimer-affected hippocampal and control samples showed that the specific activity (in units per milligram of sodium dodecyl sulfate-soluble protein) of MP-70 varied less than the activities of MP-100 and MP-130 between the two groups [15].
• One large well-conducted trial assessed docetaxel plus prednisone vs mitoxantrone plus prednisone; this showed statistically significant improvements with 3-weekly docetaxel in terms of overall survival, quality of life, pain response and PSA decline [16].
• Bicalutamide (150 mg) significantly improved time to PSA progression (HR 0.80, 95% CI 0.72 to 0.90, p <0.001) [17].
• In vivo, candesartan significantly suppressed VEGF expression, serum PSA concentration and tumor growth (1.1 +/- 0.2, 45.0 +/- 17.6 ng/ml, 235.8 +/- 37.4 mm(3)) in C4-2 xenografts in castrated mice, compared with the controls (2.4 +/- 0.6, 376.7 +/- 74.2 ng/ml, 830.8 +/- 147.6 mm(3)) [18].
• Therefore, SGZ progenitor cells committed to a neuronal phenotype before KA treatment complete their differentiation despite the rapid down-regulation of doublecortin and PSA-NCAM [19].

Other interactions of NPEPPS

• The relative expression for the aforementioned peptidases, assayed using quantitative RT-PCR, increases in CCRCC for aminopeptidases B (1.5-fold) and A (19-fold), aspartyl-aminopeptidase (3.9-fold), puromycin-sensitive aminopeptidase (2.5-fold), and pyroglutamyl peptidase I (7.6-fold) [20].
• The following lines of evidence suggest that MP100, a putative ADP receptor, and GPIIIa are distinct proteins [21].
• The puromycin-sensitive aminopeptidase was found to be resistant to proteolysis by trypsin, chymotrypsin, and protease V8 but was cleaved into an N-terminal 60-kDa fragment and a C-terminal 33-kDa fragment by proteinase K [22].
• Among genes showing an expression similar to that obtained with microarray, puromycin-sensitive aminopeptidase and teratocarcinoma-derived growth factor 3 were up-regulated in PPT and in MB, and adenomatous polyposis coli like was down-regulated only in PPT [23].

Analytical, diagnostic and therapeutic context of NPEPPS

• Puromycin-sensitive aminopeptidase. Sequence analysis, expression, and functional characterization [8].
• They were invited to have a digital rectal examination (DRE), serum PSA assay and transrectal ultrasonography (TRUS)-guided sextant prostate biopsy to see if the DRE was clinically suspicious of malignancy, the serum PSA was > or =2.1 ng/ml or free-to-total PSA (f/tPSA) ratio < or=15% [24].
• We studied the distribution of puromycin-sensitive aminopeptidase (PSA) in well-defined human brain ares by Western immunoblot in an attempt to examine its possible role in schizophrenia [25].
• Tumor volume assessed by MR imaging correlated with PSA levels (R(2) = 0.87, P < 0.001) [26].
• PSA: A Biomarker for Disease. A Biomarker for Clinical Trials. How Useful Is It [27]?

References