Down-regulation of a serine protease, myeloblastin, causes growth arrest and differentiation of promyelocytic leukemia cells

Bories, Dominique; Raynal, Marie-Cecile; Solomon, David H.; Darzynkiewicz, Zbigniew; Cayre, Yvon E.

doi:10.1016/0092-8674(89)90752-6

Cited by 275 publications

(182 citation statements)

References 55 publications

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“…PR3 is a major target Ag of antineutrophil cytoplasmic Abs (15, 16) and degrades extracellular matrix proteins (13). PR3 is also shown to activate many types of cells (12,(17)(18)(19)(20), although the underlying mechanism was unclear. Therefore, the present study may provide one of the mechanisms of the cell activation by PR3 through PAR-2, and suggests that PR3 could activate the PAR-2-expressing cells, and regulate a number of inflammatory processes, and that the control of PAR-2-activating proteinases including PR3 at inflammatory sites might be beneficial in the regulation of inflammation.…”

Section: Discussionmentioning

confidence: 99%

“…PR3 is a major target Ag of anti-neutrophil cytoplasmic Abs in Wegener's granulomatosis, a debilitating autoimmune disease characterized by necrotizing vasculitis (15,16). It has recently been shown that PR3 exhibits many biological functions, including the degradation of extracellular matrix proteins (13), regulation of myeloid differentiation (12,17), enhancement of TNF-␣ and IL-1␤ release from human monocytic cell lines (18), production of IL-8 and monocyte chemoattractant protein-1 (MCP-1) by human endothelial cells (19,20), and antibacterial action (21), all of which indicate that cell-bound and secreted soluble PR3 actively contribute to inflammatory processes, although the underlying mechanism is unclear to date.…”

mentioning

confidence: 99%

“…PR3 is a 29-kDa serine proteinase with homology to HLE and Cat G, all of which are stored in azurophil granules of neutrophils (11)(12)(13). PR3 also presents on the cell surface and within secretory and specific granules of neutrophils, and exposure of neutrophils to cytokines or chemoattractants induces an increase in cell surfacebound PR3 (14).…”

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confidence: 99%

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Activation of Human Oral Epithelial Cells by Neutrophil Proteinase 3 Through Protease-Activated Receptor-2

Uehara¹,

Sugawara²,

Muramoto

et al. 2002

The Journal of Immunology

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Proteinase 3 (PR3), a 29-kDa serine proteinase secreted from activated neutrophils, also exists in a membrane-bound form, and is suggested to actively contribute to inflammatory processes. The present study focused on the mechanism by which PR3 activates human oral epithelial cells. PR3 activated the epithelial cells in culture to produce IL-8 and monocyte chemoattractant protein-1 and to express ICAM-1 in a dose- and time-dependent manner. Incubation of the epithelial cells for 24 h with PR3 resulted in a significant increase in the adhesion to neutrophils, which was reduced to baseline levels in the presence of anti-ICAM-1 mAb. Activation of the epithelial cells by PR3 was inhibited by serine proteinase inhibitors and serum. The epithelial cells strongly express protease-activated receptor (PAR)-1 and PAR-2 mRNA and weakly express PAR-3 mRNA. The expression of PAR-2 on the cell surface was promoted by PR3, and inhibited by cytochalasin B, but not by cycloheximide. PR3 cleaved the peptide corresponding to the N terminus of PAR-2 with exposure of its tethered ligand. Treatment with trypsin, an agonist for PAR-2, and a synthetic PAR-2 agonist peptide induced intracellular Ca2+ mobilization, and rendered cells refractory to subsequent stimulation with PR3 and vice versa. The production of cytokine induced by PR3 and the PAR-2 agonist peptide was completely abolished by a phospholipase C inhibitor. 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.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Activation of Human Oral Epithelial Cells by Neutrophil Proteinase 3 Through Protease-Activated Receptor-2

Uehara¹,

Sugawara²,

Muramoto

et al. 2002

The Journal of Immunology

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“…Since activated neutrophils express PR3 on their surface [5], it could facilitate their migration through basement membranes. PR3 may be instrumental in host defense and regulation of proliferation and differentation of hematopoetic cells [2,6]. PR3 can also proteolytically process interleukin 8 into a chemotactically more potent form [7], and cleave the mammalian heat shock protein hsp28 [8].…”

Section: Introductionmentioning

confidence: 99%

Recombinant human proteinase 3, the Wegener's autoantigen, expressed in HMC‐1 cells is enzymatically active and recognized by c‐ANCA

Specks¹,

Fass²,

Fautsch³

et al. 1996

FEBS Letters

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We developed a stable expression system for conformationally intact recombinant human PR3 (rPR3) using the human mast cell line HMC-I. Like in U937 cells, the rPR3 is processed from a 34 kDa precursor to the 29 kDa mature form, primarily as the result of oligosaccharide trimming. The rPR3 binds [3H]DFP and hydrolyzes the snbstrate N-methoxysuccinylAla-Ala-Pro-Val-pNA. The enzymatic activity is inhibited by greater than 95% by al-PI. The rPR3 and the enzymatically inactive mutant rPR3-S176A are both packaged in granules. Thus, proteolytic autoprocessing is not required for PRYs targeting to granules. This rPR3 is the first to be recognized by most c-ANCA from WG patients and all anti-PR3 ANCA that were detected by standard anti-PR3 specific ELISA. This expression system for rPR3 represents a versatile tool for the analysis of its intraceHular processing, structure-function relationships and interaction with autoantibodies.

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“…Amino acid residues at positions 103, 119, and 120 are polymorphic in human populations, accounting for three different protein sequences (V103 or I103 in combination with A119 and T120, and I103 in combination with T119, S120). Evolutionary comparisons, however, suggest that V103, A119, and T120 (20)(21)(22) of hPR3 represent the ancestral allele (Fig. 2).…”

Section: Strategy For Mapping Conformational Epitopesmentioning

confidence: 99%

Mapping of Conformational Epitopes on Human Proteinase 3, the Autoantigen of Wegener’s Granulomatosis

Kuhl

Korkmaz

Utecht³

et al. 2010

The Journal of Immunology

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Anti-neutrophil cytoplasmic Abs (cANCAs) against conformational epitopes of proteinase 3 (PR3) are regarded as an important pathogenic marker in Wegener’s granulomatosis (WG). Although the three-dimensional structure of PR3 is known, binding sites of mAbs and cANCAs have not been mapped to date. Competitive binding and biosensor experiments suggested the existence of four nonoverlapping areas on the PR3 surface. In this paper, we present an approach to identify these discontinuous surface regions that cannot be mimicked by linear peptides. The very few surface substitutions found in closely related PR3 homologs from primates, which were further varied by the construction of functional human-gibbon hybrids, resulted in the differential loss of three Ab binding sites, two of which were mapped to the N-terminal β-barrel and one to the linker segment connecting the N- and C-terminal barrels of PR3. The sera from WG patients differed in their binding to gibbon PR3 and the gibbon-human PR3 hybrid, and could be divided into two groups with similar or significantly reduced binding to gibbon PR3. Binding of almost all sera to PR3–α1-protease inhibitor (α1–PI) complexes was even more reduced and often absent, indicating that major antigenic determinants overlap with the active site surface on PR3 that associates with α1-PI. Similarly, the mouse mAbs CLB12.8 and 6A6 also did not react with gibbon PR3 and PR3–α1-PI complexes. Our data strongly suggest that cANCAs from WG patients at least in part recognize similar surface structures as do mouse mAbs and compete with the binding of α1-PI to PR3.

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Down-regulation of a serine protease, myeloblastin, causes growth arrest and differentiation of promyelocytic leukemia cells

Cited by 275 publications

References 55 publications

Activation of Human Oral Epithelial Cells by Neutrophil Proteinase 3 Through Protease-Activated Receptor-2

Activation of Human Oral Epithelial Cells by Neutrophil Proteinase 3 Through Protease-Activated Receptor-2

Recombinant human proteinase 3, the Wegener's autoantigen, expressed in HMC‐1 cells is enzymatically active and recognized by c‐ANCA

Mapping of Conformational Epitopes on Human Proteinase 3, the Autoantigen of Wegener’s Granulomatosis

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