Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.4 (trypsin)
 42,187 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The liver is where lymphocytes undergo activation-induced cell death (AICD) at the resolution phase of an immune response, which is crucial for homeostasis of the immune system and prevention of autoimmunity. Exploring the machinery of AICD in the liver, we found that a primary culture supernatant of murine hepatocytes had an antiproliferative effect on antigen-stimulated T clone and T lymphoma cells. Biological study showed that the antiproliferation was due to induction of apoptosis in a caspase-dependent manner. The apoptosis-inducing potential was sensitive to trypsin, heat (> 70 degrees ) and acid (< pH 5) treatment but could not be neutralized by anti-tumour necrosis factor-alpha, anti-Fas ligand, or anti-transforming growth factor-beta antibodies. Biochemical study of the isolated and purified apoptosis-inducing component from the supernatant showed that it was a protein with a molecular mass of about 68,000-70,000. It induced apoptotic change in murine T and B cells, and to a lesser degree, in human lymphoid cells, but not in macrophages. Biochemical and biological characteristics distinguish this protein from others that have been reported to induce apoptosis of lymphocytes. The identification of an apoptosis-inducing protein derived from murine hepatocytes, which selectively induces apoptosis in lymphocytes, suggests one possible mechanism for immune suppression in the liver.
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PMID:Apoptosis-inducing protein derived from hepatocyte selectively induces apoptosis in lymphocytes. 1251 10

alpha2-Macroglobulin (alpha2M) is a protease inhibitor that has separate binding sites for transforming growth factor-beta (TGF-beta) and beta-amyloid peptide (Abeta), both of which have been identified in the beta2M sequence. In the 3D-structure of alpha2M, TGF-beta occupies the alpha2M central cavity, overlapping with the space that can accommodate up to two molecules of protease. As a result, ternary alpha2M-protease complexes (2 mol protease/mol alpha2M) have been reported to not bind TGF-beta. The goal of the present study was to test whether binding of Abeta to alpha2M is controlled by steric constraints imposed by associated proteases, similarly to TGF-beta. We confirmed that binary alpha2M-trypsin complex (1 mol trypsin/mol alpha2M) binds increased amounts of TGF-beta1, compared with native alpha2M, while ternary alpha2M-trypsin complex binds substantially decreased amounts of TGF-beta1. By contrast, Abeta-binding to binary and ternary alpha2M trypsin complex was equivalent. In both cases, binding was substantially increased compared with the negligible level observed with native alpha2M. Plasmin is a large protease (Mr approximately 82,000) that substantially occupies the alpha2M central cavity; however, alpha2M-plasmin complex also bound increased amounts of Abeta, compared with native alpha2M. We conclude that Abeta accesses its binding site, in alpha2M, from outside the alpha2M central cavity. The TGF-beta- and Abeta-binding sites are spatially separated not only in the primary sequence of alpha2M, but also in the 3D-structure.
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PMID:Beta-amyloid peptide binds equivalently to binary and ternary alpha2-macroglobulin-protease complexes. 1600 50

Mouse mast cell protease-7 (mmcp-7) is a tryptase predominantly expressed in differentiated connective tissue-type mast cells. Previous study revealed that transforming growth factor-beta (TGF-beta) increases gene transcript of mmcp-7 in mast cells. The present study explored molecular mechanism of the up-regulation of mmcp-7 by TGF-beta. Luciferase-based reporter assays using deletion and point mutations of mmcp-7 promoter showed a critical region spanning nt -126 to -122 relative to the transcriptional start site, a Smad-binding element, for transcriptional activation by the TGF-beta pathway. In addition, a region from nt -104 to -98, a TPA-responsive element, was also necessary for the transactivation. Consistent with the current model for the TGF-beta signaling, Smad4 was required for the transcription of mmcp-7 by Smad3, a signal mediator of TGF-beta. Treatment with TGF-beta in mast cells resulted in the differential gene induction of the AP-1 components, i.e., transient induction of c-fos but not of c-jun and junB. Expression of c-fos further enhanced Smad3 and Smad4-induced transcription of mmcp-7, whereas c-jun expression inhibited the transcription. Our results suggest that TGF-beta stimulates mmcp-7 transcription through the Smad3-Smad4 pathway as well as c-fos induction, and that the AP-1 components distinctly related with the TGF-beta pathway.
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PMID:Transcriptional regulation of mouse mast cell protease-7 by TGF-beta. 1673 Aug 10

Coagulation proteases have been suggested to play a role in the pathogenesis of tissue remodeling and fibrosis. We therefore assessed the proinflammatory and fibroproliferative effects of coagulation protease factor (F)Xa. We show that FXa elicits a signaling response in C2C12 and NIH3T3 fibroblasts. FXa-induced ERK1/2 phosphorylation was dependent on protease-activated receptor (PAR)-2 cleavage because desensitization with a PAR-2 agonist (trypsin) but not a PAR-1 agonist (thrombin) abolished FXa-induced signal transduction and PAR-2 siRNA abolished FXa-induced ERK1/2 phosphorylation. The PAR-2-dependent cellular effects of FXa led to fibroblast proliferation, migration, and differentiation into myofibroblasts, as demonstrated by the expression of alpha-smooth muscle actin and desmin, followed by the secretion of the cytokines monocyte chemotactic protein-1 and interleukin-6 as well as the expression of the fibrogenic proteins transforming growth factor-beta and fibronectin. To assess the relevance of FXa-induced proliferation and cell migration, we examined the effect of FXa in a wound scratch assay. Indeed, FXa facilitated wound healing in a PAR-2- and ERK1/2-dependent manner. Taken together, these results support the notion that, beyond its role in coagulation, FXa-dependent PAR-2 cleavage might play a role in the progression of tissue fibrosis and remodeling.
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PMID:Factor Xa stimulates proinflammatory and profibrotic responses in fibroblasts via protease-activated receptor-2 activation. 1820 98


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