Disease relevance of PRTN3

• Autoantibodies against PR3 are an obligate feature in the pathogenesis of Wegener's granulomatosis, a systemic autoimmune vasculitis [1].
• This makes PR3 a very intriguing protein with a large array of physiological functions, some of which may play a role in ANCA-associated vasculitidis and myeloid leukemia [2].
• Furthermore, PR3 is overexpressed in a variety of acute and chronic myeloid leukemia cells [2].
• Release of immunoreactive human neutrophil proteinase 4, normally and in peritonitis [3].
• We conclude that PR-3 may be important in the pathogenesis of human emphysema [4].

Psychiatry related information on PRTN3

• The loss of cortical cholinergic innervation in senile dementia of the Alzheimer's type (SDAT) is associated with cell loss in the nucleus basalis and related cell groups (magnocellular basal nucleus, MBN) [5].
• Sixty individuals seeking outpatient treatment for marijuana dependence were randomly assigned to 1 of 3 treatments: motivational enhancement (M), M plus behavioral coping skills therapy (MBT), or MBT plus voucher-based incentives (MBTV) [6].

High impact information on PRTN3

• Associated metabolic events and the loss of endothelial barrier properties suggest that anti-PR3-induced activation of endothelial cells may contribute to the pathogenetic sequelae of autoimmune vasculitis characterizing WG [7].
• We conclude that anti-PR3 antibodies are potent inductors of the preformed phosphoinositide hydrolysis-related signal tranduction pathway in human endothelial cells [7].
• Anti-neutrophil cytoplasmic antibodies (ANCAs) targeting proteinase 3 (PR3) have a high specifity for Wegener's granulomatosis (WG), and their role in activating leukocytes is well appreciated [7].
• Priming of HUVECs with tumor necrosis factor alpha induced endothelial upregulation of PR3 message and surface expression of this antigen, as measured by Cyto-ELISA, with a maximum occurrence after 2 h [7].
• When TNF-alpha-primed neutrophils were stimulated by anti-PR3 antibodies, superoxide and elastase secretion was provoked in the absence of lipid mediator generation [8].

Chemical compound and disease context of PRTN3

• Proteinase 3 (PR-3) is a human polymorphonuclear leukocyte (PMNL) serine proteinase that degrades elastin in vitro and causes emphysema when administered by tracheal insufflation to hamsters (Kao, R. C., Wehner, N. G., Skubitz, K. M., Gray, B. H., and Hoidal, J. R. (1988) J. Clin. Invest. 82, 1963-1973) [9].
• We report here that expression of proteinase 3 (PR3), a serine protease, is down-regulated in the HL60/ADR multidrug resistant variant of the human myelogenous leukemia cell line HL-60, and that down-regulation of PR3 is associated with doxorubicin (DOX) resistance in these cells [10].
• Our data give a hint at a PR-3 antibody-mediated mechanism of endothelial injury via antibody-dependent cellular cytotoxicity in WG and other ANCA-related vasculitides [11].
• In a hamster model of N-methyl-N-benzylnitrosamine (MBN)-induced oral carcinogenesis, the incidence of buccal pouch (HBP) carcinomas in MBN-treated hamsters (17.8+/-7.5) was significantly higher than MBN-treated hamsters given tea (10.8+/-3.9) (P<0.05) [12].
• Positive classic antineutrophil cytoplasmic antibody (C-ANCA) titer at switch to azathioprine therapy associated with relapse in proteinase 3-related vasculitis [13].

Biological context of PRTN3

• (PRTN3, myeloblastin) was localized to chromosomal band 19p13.3 by radioactive and fluorescent in situ hybridization (FISH) to normal metaphase chromosomes [14].
• The five exons of AZU and PR3 are organized like those of NE and other granule-associated serine proteases of hematopoietic cells [15].
• We report a physical map of the gene cluster, its location on chromosome 19pter, and the exon-intron organization of the AZU and PR3 genes [15].
• We have isolated several cosmid clones each of which contains the functional genes for AZU, PR3, and NE in this order [15].
• The 400-base pair (bp) 5'-flanking sequence of the PR-3 gene contains a TATA box at position 379 [16].

Anatomical context of PRTN3

• NE, PR3, and AZU are coordinately downregulated in the premonocytic cell line U937 during induced terminal differentiation [15].
• Proteinase-3 (PR-3) is a neutral serine proteinase present in the azurophil granules of human polymorphonuclear leukocytes [16].
• Recently, we reported that a neutrophil-derived serine proteinase, proteinase 3 (PR3), activated human oral epithelial cells through PAR-2 [17].
• In this study, we present evidence for the critical role of proteinase-3 (PR3) in the proliferation of myeloid cells via the proteolytic regulation of the cyclin-dependent kinase inhibitor p21(waf1) [18].
• Employing double immunofluorescence confocal microscopy, subcellular fractionation, and co-immunoprecipitation, we found that PR3 and p21 colocalized in the cytosol [18].

Associations of PRTN3 with chemical compounds

• The NH2-terminal sequence and the amino-acid composition of NP4 were distinct from those of elastase and cathepsin G [19].
• NP4 was purified and electrophoresis of the affinity-purified enzyme in sodium dodecyl sulfate polyacrylamide gels resulted in a single Mr = 30,000 polypeptide [19].
• The expression of PAR-2 on the cell surface was promoted by PR3, and inhibited by cytochalasin B, but not by cycloheximide [20].
• Treatment of intact azurophil granules with [3H]diisopropyl fluorophosphate resulted in labeling of elastase, cathepsin G, and AGP7, whereas azurocidin was not labeled [21].
• The analysis of peptides generated by PR-3 digestion of insulin chains and the activity profile against a panel of chromogenic synthetic peptide substrates show that PR-3 prefers small aliphatic amino acids (alanine, serine, and valine) at the P1 site [9].

Physical interactions of PRTN3

• Three PR3 MoAbs showed no binding to unstimulated or TNF-alpha-stimulated HUVEC either by ELISA or by indirect immunofluorescence staining [22].
• The NB1-bound PR3 was active and was cleared from the surface by alpha-1-protease inhibitor [23].

Enzymatic interactions of PRTN3

• During in vitro studies, purified p21 was cleaved by PR3, resulting in a 10-kDa p21 fragment [18].
• PR3 cleaved the peptide corresponding to the N terminus of PAR-2 with exposure of its tethered ligand [20].
• In vitro, purified PR3 cleaved procaspase-3 into an active 22-kDa fragment [24].

Regulatory relationships of PRTN3

• Proper selection of the primary specificity group (R(I)) was found to lead to selective inhibition of HLE over Cat G, however, those compounds that inhibited HLE also inhibited PR 3, albeit less efficiently [25].
• LPS mediated TNF-alpha production in whole blood was significantly inhibited when preincubated with PR3 [26].
• The present study was conducted to investigate if proteinase-3 (PR3) is able to influence lipopolysaccharide (LPS) responses of monocytes via degradation of CD14 and if antineutrophil cytoplasmic antibodies (ANCA) may modify this process [26].
• These findings suggest that neutrophil PR3 activates oral epithelial cells through G protein-coupled PAR-2 and actively participates in the process of inflammation such as periodontitis [20].
• CONCLUSION: This study showed that anti-PR3 treatment of HUVEC induces sequential expression of IL-1alpha mRNA and TF mRNA, as well as their corresponding proteins [27].

Other interactions of PRTN3

• This finding suggested that the augmented release was attributable to PR3 but not NE nor Cat G [28].
• The physiopathological implications of the cleavage of p21 by PR3 have to be determined [18].
• PR3 and MPO are colocalized in the azurophilic granules of neutrophils and translocated to the cell surface during activation and thus are able to interact with ANCA after neutrophil preactivation [29].
• By IFA on alcohol-fixed neutrophils, monoclonal and polyclonal anti-BPI antibodies produced a C-ANCA pattern, whereas rabbit anti-azurocidin antibody produced a P-ANCA pattern [30].
• It is of importance that anti-neutrophil cytoplasmic antibodies (ANCA) in patients with Wegener's granulomatosis (WG) are mainly directed against PR3 only [2].
• We conclude that PR3 membrane expression on neutrophils is mediated by the NB1 receptor [31].

Analytical, diagnostic and therapeutic context of PRTN3

• This review will focus on PR3 and the characteristics of PR3 that might implicate this particular antigen in the pathogenesis of WG and as target for immunotherapy in myeloid leukemias [2].
• By ELISA, sera from 229 P-ANCA-positive patients, 99 C-ANCA-positive patients and 48 ANCA-negative (by IFA) patients with renal biopsies were tested for reactivity with recombinant human BPI and purified human azurocidin [30].
• The major subtypes of anti-neutrophil cytoplasmic antibodies (ANCA) detected by indirect immunofluorescence assay (IFA) are P-ANCA and C-ANCA [30].
• Immunohistochemistry showed that inflamed oral epithelium actually expresses PR3 protein [32].
• Azurocidin and AGP7 represent significant protein components of the azurophil granule, together comprising approximately 15% of the acid-extractable protein as judged by reverse-phase high performance liquid chromatography analysis [21].

References