Disease relevance of Cma1

• Mast cell chymase induces expression of chemokines for neutrophils in eosinophilic EoL-1 cells and mouse peritonitis eosinophils [1].
• A comparison with the corresponding region of the rat mucosal mast cell-specific protease RMCP-II is presented. cDNA clones for the mast cell proteases MMCP-4 (950 bp) and MMCP-5 (1098 bp) were isolated from a cDNA library of a connective tissue mast cell-like mouse mastocytoma cell line [2].
• Immunocytochemical staining localized MMCP-5 to the cytoplasmic granules of serosal mast cells and Kirsten sarcoma virus-immortalized mouse mast cells [3].
• Isoform-selective upregulation of mast cell chymase in the development of skin fibrosis in scleroderma model mice [4].
• These findings suggest that mast cell chymase and tryptase participate in the acute inflammation and remodeling process of viral myocarditis [5].

High impact information on Cma1

• To gain insight into the biological role of mast cell chymase we have generated a mouse strain with a targeted deletion in the gene for mast cell protease 4 (mMCP-4), the mouse chymase that has the closest relationship to the human chymase in terms of tissue localization and functional properties [6].
• Perivascular fibrosis and upregulation of mast cell chymase were all less apparent in W/W(v) mice [7].
• Soybean trypsin inhibitor and succinyl-L-Ala-Ala-Pro-Phe-chloromethylketone, which inhibit mast cell chymase, prevented progelatinase activation [8].
• Dog mastocytoma cells secrete a 92-kD gelatinase activated extracellularly by mast cell chymase [8].
• Because MMCP-5 is a chymase and MMCP-6 a tryptase, there was a possibility that the difference in regulation mechanisms was associated with their different characteristics as proteases [9].

Chemical compound and disease context of Cma1

• Mast cell chymase and tryptase were purified from dog mastocytoma cells [10].
• cDNAs were isolated that encode mouse mast cell protease-5 (MMCP-5), an approximately 30,000 Mr serine protease stored in the secretory granules of serosal mast cells (SMC) and Kirsten sarcoma virus-immortalized mast cells [11].
• Taken together, these observations suggest that mast cell chymase may contribute to development of the DNFB-induced dermatitis, probably by promoting eosinophil infiltration [12].
• The observation defines a novel cell-dependent mechanism that blocks the initial steps of reverse cholesterol transport and suggests a role for mast cell chymase in cellular accumulation of cholesterol, an early stage in atherogenesis [13].

Biological context of Cma1

• The +-MITF appeared to regulate the transactivation of the MMCP-5 gene indirectly [14].
• Although +-MITF directly bound CANNTG motifs in the promoter region of the MMCP-6 gene and transactivated it, the binding of +-MITF to the CAGTTG motif in the promoter region of the MMCP-5 gene was not detectable [14].
• We reported that expression of the mouse mast cell protease 5 (MMCP-5) and MMCP-6 genes were deficient in cultured mast cells (CMC) derived from mutant mice of mi/mi genotype [9].
• Based on the deduced amino acid sequences of these cDNAs, MMCP-5 is synthesized as a 247-amino acid preproenzyme composed of a novel 19-residue hydrophobic signal peptide, a Gly-Glu activation peptide not present in other mast cell chymases, and a 226-amino acid protein that represents the mature enzyme [11].
• Moreover, the results suggest an important role for mast cell chymase in regulating connective tissue homeostasis [15].

Anatomical context of Cma1

• Mast cell chymase is known to induce eosinophil migration in vivo and in vitro [16].
• The highest concentration of MMCP-5 was found in the most electron-dense secretory granules of the cells [3].
• Because mouse bone marrow-derived mast cells express abundant amounts of MMCP-5 mRNA, anti-MMCP-5(146-162) Ig was used to study the translation and granule accumulation of this protease when progenitor cells differentiate into these immature mouse mast cells [3].
• Maximal expression of MMCP-5 mRNA occurred after bone marrow cells had been cultured for 2 wk in IL-3-rich WEHI-3 cell conditioned medium, and MMCP-5 protein was detected in these cells [3].
• The mMCP-6 and mMC-CPA genes are located on chromosomes 17 and 3, respectively, whereas the four mast cell chymase genes all reside on chromosome 14 linked to a gene complex that encodes four cytotoxic T lymphocyte granzymes [17].

Associations of Cma1 with chemical compounds

• Here we present the cloning of three novel mouse mast cell-specific serine proteases, MMCP-1, MMCP-4 and MMCP-5 [2].
• Taken together, these data show that, after salt extraction and a single benzamidine affinity chromatography step, both mast cell chymase and tryptase can be separated and in case of chymase also highly purified, allowing thus for the study of biological activities of this molecule [18].
• Altered processing of fibronectin in mice lacking heparin. a role for heparin-dependent mast cell chymase in fibronectin degradation [19].
• Depletion of pre beta 1LpA1 and LpA4 particles by mast cell chymase reduces cholesterol efflux from macrophage foam cells induced by plasma [20].
• Role of mast cell chymase in allergen-induced biphasic skin reaction [21].

Enzymatic interactions of Cma1

• Further experiments showed that the degradation of fibronectin observed in cell cultures from NDST-2(+/+) mice was catalyzed by mast cell chymase in a strongly heparin-dependent manner [19].

Regulatory relationships of Cma1

• Mast cell chymase degrades apoE and apoA-II in apoA-I-knockout mouse plasma and reduces its ability to promote cellular cholesterol efflux [22].

Other interactions of Cma1

• We compared the regulation mechanisms of another chymase, MMCP-4, with those of MMCP-5 and MMCP-6 [9].
• Analysis of the amino acid composition reveals a positive net charge for all three proteases MMCP-1 +3, MMCP-4 +18 and MMCP-5 +12) [2].
• In contrast, BMMC developed with rKL alone or by sequential culture in medium containing rIL-3 followed by rKL expressed high levels of MMCP-4 and -6 mRNA, as well as the transcripts that encode MMCP-5 and MC-CPA [23].
• Functionally, capsaicin applied to forearm skin revealed by 6 h discharge of mast cell chymase and induction of E-selectin in adjacent microvascular endothelium, events consistent with release of substance P from axons and subsequent stimulation of cytokine-mediated mast cell-endothelial interaction [24].
• Involvement of mast cell chymase in bleomycin-induced pulmonary fibrosis in mice [25].

Analytical, diagnostic and therapeutic context of Cma1

• After affinity purification, anti-MMCP-5(146-162) Ig reacted in SDS-PAGE immunoblots to recombinant MMCP-5 and to the native MMCP-5 protein present in the lysates of mouse serosal mast cells and the MC5 line of Kirsten sarcoma virus-immortalized mouse mast cells [3].
• Male DBA/2 mice were inoculated intraperitoneally with the encephalomyocarditis virus and the gene expression of mast cell chymase, mouse mast cell protease (mMCP)-4 and -5, and tryptase, mMCP-6, matrix metalloproteinase (MMP)-9 and type-I procollagen was measured by real-time quantitative RT-PCR analysis [5].

References