Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.73 (urokinase-type plasminogen activator)
 10,685 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lysophosphatidylcholine (lysoPC) is implicated in the development of atherosclerosis and certain autoimmune diseases, and is reported to induce tissue-type plasminogen activator (tPA) at the protein level in endothelial cells. This study was designed to investigate the effect of lysoPC on tPA gene expression and the underlying molecular mechanisms in cultured endothelial cells. LysoPC transiently induced the mRNA expression of tPA in endothelial cells. LysoPC also induced the mRNA expression of urokinase-type plasminogen activator (uPA), uPA receptor, and plasminogen activator inhibitor-1, but the kinetics were different from that of tPA. Promoter analysis revealed that the cyclic AMP-responsive element of the tPA gene (tPACRE) is required for lysoPC-induced tPA expression. Furthermore, an electrophoresis mobility shift assay showed that lysoPC increased the binding activity of CRE binding protein to tPACRE. These results indicated that lysoPC transcriptionally upregulated the gene expression of tPA in endothelial cells, at least in part, via tPACRE activation.
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PMID:Lysophosphatidylcholine induces tPA gene expression through CRE-dependent mechanism. 1572 Dec 75

The effects of two bovine beta-casein peptides on the urokinase plasminogen activator (u-PA) system and superoxide anion (SA) production by porcine macrophages and neutrophils activated by phorbol myristate acetate (PMA) were investigated. Macrophages and neutrophils were obtained from fourteen weaned piglets and were cultured in vitro for 24 h with or without one of two chemically synthesised peptides: tripeptide leucine-leucine-tyrosine (residues 191-193 of beta-casein) (LLY) and hexapeptide proline-glycine-proline-isoleucine-proline-asparagine (residues 63-68 of beta-casein). Following incubation, cells were stimulated with 80 microM-PMA. Total cell-associated u-PA, membrane-bound u-PA, free u-PA binding sites along with SA production were determined after stimulation with PMA. Both peptides suppressed the u-PA system and SA production of PMA-stimulated macrophages isolated from piglets during weeks 1-2 after weaning. Only the tripeptide LLY suppressed the u-PA system and SA production of PMA-stimulated neutrophils during the same time period. None of the peptides tested had any effect (P>0.05) on the u-PA system and SA production of PMA-stimulated macrophages and neutrophils isolated from the same piglets during weeks 5-6 after weaning. Thus, peptides are effective only in the early post-weaning period. Using cyclic AMP analogues that are highly specific activators of protein kinase A (PKA) or exchange protein directly activated by cyclic AMP-1 (Epac-1), we found that activation of PKA, but not Epac-1, was responsible for the downregulation of the u-PA system, whereas activation of PKA and/or Epac-1 was responsible for the downregulation of SA system in both macrophages and neutrophils.
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PMID:The effect of two bovine beta-casein peptides on various functional properties of porcine macrophages and neutrophils: differential roles of protein kinase A and exchange protein directly activated by cyclic AMP-1. 1692 62

Previous studies have suggested that cathepsin B participates in the joint destruction associated with rheumatoid arthritis (RA). This study examined the activity of cathepsin B (a lysosomal cysteine protease) in human osteoblasts along with its regulation by cyclic AMP and Interleukin-6 (IL-6). Cyclic AMP elevating agents activate cathepsin B and stimulate the secretion of cathepsin B via the secretion of IL-6, a potent mediator of RA. This study investigated the induction of cathepsin B using the proinflammatory cytokine in human osteoblasts (MG-63) in relation to p38 mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-kappa B transcription factor. When added to MG-63 cells, IL-6 stimulated the production of cathepsin B, which was reduced significantly by the addition of SB203580, a specific p38 MAPK inhibitor. In addition, the release of IL-6 was also inhibited by either pyrrolidine dithiocarbamate (PDTC) or NF-kappaB SN50, which are potent NF-kappaB inhibitors. Both NF-kappaB inhibitors had a larger inhibitory effect on the activity of cathepsin B in the presence of SB203580. IL-6 stimulated the NF-kappaB binding affinity as well as the activation of p38 MAP kinase, leading to the release of cathepsin B. However, SB203580 had no effect on the IL-6-induced activation of NF-kappaB, and neither of the NF-kappaB inhibitors decreased the level of p38 MAPK activation in the IL-6-stimulated osteoblasts. Moreover, IL-6 increased the activity of urokinase type plasminogen activator (uPA) in MG-63 cells, which was inhibited by SB203580, PDTC and NF-kappaB SN50. This strongly suggests that p38 MAPK and NF-kappaB are essential to the IL-6-induced activation of cathepsin B or uPA and that these two IL-6-activated pathways can act independently.
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PMID:Interleukin-6 and cyclic AMP stimulate release of cathepsin B in human osteoblasts. 1784 65

Activating transcription factor 3 (ATF3) is a member of the ATF/cyclic AMP response element-binding family of transcription factors. We present evidence that ATF3 has a dichotomous role in cancer development. By both gain- and loss-of-function approaches, we found that ATF3 enhances apoptosis in the untransformed MCF10A mammary epithelial cells, but protects the aggressive MCF10CA1a cells and enhances its cell motility. Array analyses indicated that ATF3 upregulates the expression of several genes in the tumor necrosis factor pathway in the MCF10A cells but upregulates the expression of several genes implicated in tumor metastasis, including TWIST1, fibronectin (FN)-1, plasminogen activator inhibitor-1, urokinase-type plasminogen activator, caveolin-1 and Slug, in the MCF10CA1a cells. We present evidence that ATF3 binds to the endogenous promoters and regulates the transcription of the TWIST1, FN-1, Snail and Slug genes. Furthermore, conditioned medium experiments indicated that ATF3 has a paracrine/autocrine effect, consistent with its upregulation of genes encoding secreted factors. Finally, ATF3 gene copy number is >2 in approximately 80% of the breast tumors examined (N=48) and its protein level is elevated in approximately 50% of the tumors. These results provided a correlative argument that it is advantageous for the malignant cancer cells to express ATF3, consistent with its oncogenic roles suggested by the MCF10CA1a cell data.
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PMID:A potential dichotomous role of ATF3, an adaptive-response gene, in cancer development. 1795 19

We showed, using the method of lysis of fibrin plates and five substrate proteins in a thin layer of agar gel, that inorganic orthophosphate (0.001-0.06 M) enhances by 50-250% the activatory functions of streptokinase, urokinase, and tissue plasminogen activator and, in general, by 1.2-12.0 times enhances protein lysis by trypsin, alpha-chymotrypsin, subtilisin, papain, bacterial metalloprotease, and even pepsin at a concentration < 4 mM. At higher concentrations, phosphate sharply inhibited pepsin activity and inhibited by 40-50% gelatin lysis by papain and gelatin (at a peak concentration) and casein lysis by metalloprotease. Inorganic pyrophosphate ions at concentrations of 10(-8)-10(-1) M enhanced the cleavage of a number of proteins by serine proteases and, at concentrations of 10(-5) -10(-3) M, the activities of pepsin, plasminogen tissue activator, and streptokinase by 100 and 40%, respectively. The pyrophosphate concentrations of > 10(-3) and >10(-4) M inhibited pepsin- and metalloprotease-induced lysis of virtually all proteins. ATP increased casein lysis by serine proteases, metalloprotease, and pepsin by 20-60% at concentration of 10(-3) M and by 30-260% at 10(-2) M concentration. At concentrations of 10-2 M, it inhibited the cleavage of some proteins by trypsin, chymotrypsin, papain, and metalloprotease by 20-100%, and, at concentrations of 10(-3) M, lysis of albumin with pepsin and other proteins (except for fibrinogen) by metalloprotease. A GTP concentration of 10(-7)-10(-2) M increased protein degradation by serine proteases, papain, and gelatin lysis by pepsin by 20-90%, whereas albumin lysis was inhibited by 40-70%. The presence of 10(-6)-10(-5) M GTP led to a slightly increased degradation of hemoglobin and casein by bacterial metalloprotease, while 10(-3) M GTP induced a drop in the activity of the metalloprotease by 20-50%. ADP could enhance gelatin lysis by trypsin, casein lysis by pepsin and papain, and inhibited metalloprotease activity by 20-100% (at 10(-3) M). Peculiarities of the effects of AMP and GD(M)P on gelatin lysis were found.
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PMID:[Effects of biogenic phosphates on protease-induced protein cleavage and functioning of plasminogen activators]. 1867 89


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