Disease relevance of Prtn3

• Antineutrophil cytoplasmic autoantibodies (ANCAs) recognizing human proteinase 3 of neutrophil granules are a diagnostic hallmark of Wegener granulomatosis, an autoimmune systemic vasculitis with predilection for the respiratory tract and kidneys [1].
• Myeloblastin is involved in the control of proliferation in myeloid leukemia cells [2].
• L-658,758 effectively inhibited elastinolysis by NE, proteinase-3 and the pooled sol but did not inhibit the activity of the metalloelastases, human and mouse macrophage metalloelastase and Pseudomonas elastase [3].
• This new finding was discovered serendipitously using material from patients with inflammatory vascular disease caused by antineutrophil cytoplasmic autoantibodies (ANCA) with specificity for proteinase-3 (PR-3) [4].
• Anti-neutrophil cytoplasmic Abs, directed primarily toward myeloperoxidase (MPO) and proteinase 3, are detected in the majority of patients with distinct forms of small vessel vasculitides and pauci-immune necrotizing glomerulonephritis [5].

High impact information on Prtn3

• In neutrophils, NE is stored in azurophil granules along with other serine proteinases (cathepsin G, proteinase 3 and azurocidin) at concentrations exceeding 5 mM [6].
• Myeloblastin is a granulocyte colony-stimulating factor-responsive gene conferring factor-independent growth to hematopoietic cells [7].
• Altogether, the data offer a clue as to how a myeloid-specific transcriptional machinery can be accessible to regulation by retinoic acid and point to myeloblastin as a novel target of Myb [2].
• Myb is shown to induce myeloblastin expression and abolish its down-regulation by retinoic acid [2].
• The myeloblastin promoter contains PU.1, C/EBP, and Myb binding sites, each of which are critical for constitutive expression in myeloid cells [2].

Chemical compound and disease context of Prtn3

• This link between Myb and myeloblastin suggests a previously nonidentified Myb pathway through which growth arrest is induced by retinoic acid in myeloid leukemia cells [2].
• The existence of a subset of PMN which spontaneously expresses PR3 and varies among individuals, may be relevant to the pathogenesis of anti-PR3 ANCA autoantibody-related vasculitis [8].

Biological context of Prtn3

• A comparison between the mouse and human PR-3 cDNA reveals 73% homology, however, this drops to 60% when the amino acid sequences are compared [9].
• This enhancer is located in the second intron of the proteinase-3 gene and so may regulate more than one gene in the myeloid protease cluster [10].
• 1. Moreover, a GC-rich region, similar to a cis-element in the proteinase 3 promoter, was identified [11].
• Comparison of mouse PR3 genomic structure with that of its human counterpart indicates that: 1) the mPR3 gene spans 7 kb organized in 5 exons and 4 introns, 2) the codons of His-Asp-Ser of the catalytic site are conserved and spread out over different exons, similar to the human gene, and 3) the gene product encodes a pre-proform of the protein [12].
• Interestingly enough, mutation of Y-28 to S (mutation Y28S) in the zinc finger results in RNA packaging at a level similar to that observed upon deletion of three prolines and three arginines in the C-terminal domain of NCp10 (mutant delta PR3) [13].

Anatomical context of Prtn3

• Proteinase 3 was expressed in several cell lines of myelo-monocytic origin and in one B-cell line, but not in any of the other cell lines tested [14].
• Proteinase 3 (PR3) is a neutrophil serine protease stored in the azurophil granules of the promyelocyte and its successors [15].
• They are localized in the azurophil granules, together with proteinase 3 and the acid cathepsins B and D. In addition neutrophils contain collagenase in the specific granules, acid proteinases in the C-particles and plasminogen activator in organelles with the characteristics of secretory vesicles [16].
• PAR-2 is expressed in airway epithelial cells, where they are activated by mast cell tryptase, neutrophil proteinase 3, or trypsin [17].

Associations of Prtn3 with chemical compounds

• In contrast, our findings suggest that the three subgroups, including (1) GzmK and the potent apoptosis-inducing GzmA, (2) the neutrophil proteases (proteinase 3, N-elastase and azurocidin), and (3) adipsin, have all evolved as distinct groups before the separation of tetrapods from the ray-finned fish approximately 420 million years ago [18].
• Three months after a boost injection with the human AECA, mice developed endogenous AECA (AB), but not Abs to proteinase-3, cardiolipin, or DNA [19].
• Other enzymes represented, but at lower levels, included elastase IV, proteinase 3, complement C2, chymotrypsin B, chymotrypsin-like protein, and Hageman factor [20].
• Enzymatic activation of PR3 was suggested by affinity to diisopropylfluorophosphate and removal of an amino-terminal propeptide [15].
• Furthermore, coadministration of exogenous murine PR3 or a synthetic PAR2 agonist (ASKH95) with LPS in the anti-Gr-1-treated mice restored the serum IL-18 levels to those in control mice treated with P. acnes and LPS [21].

Other interactions of Prtn3

• These results suggest that Stat6-protease may belong to the elastase family but differs from NE or PR3 [22].
• Characterization of cDNA clones encoding mouse proteinase 3 (myeloblastine) and cathepsin G [14].
• The microarray results suggested that expression of myeloperoxidase and proteinase-3 might be used to identify CD45+ side population cells [23].

Analytical, diagnostic and therapeutic context of Prtn3

• Using a polymerase chain reaction (PCR)-based strategy for the isolation of trypsin-related serine proteases, we were able to isolate cDNAs for two of the major neutrophil and monocyte serine proteases in the mouse, cathepsin G and mouse protease 3 (myeloblastin) [14].
• Mobility gel shift analysis of DNA-protein complexes using competitor DNAs verified the involvement of both OXBOX- and REBOX-binding factors in PR3 [24].
• The stable expression of transgenic proteinase 3 was characterized by biosynthetic labeling, followed by immunoprecipitation, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and fluorography [15].
• Translocation of PR3 to granules was shown by subcellular fractionation and immunocytochemistry [15].
• The proportion of PR3-positive and -negative PMN, observed by flow cytometry with anti-PR3 mAbs or ANCA autoantibodies, varies among individuals but is extremely stable for each individual over prolonged time periods [8].

References