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)

Cancer-associated or reactive stromal cells are composed of endothelial and inflammatory cells as well as of spindle cells such as fibroblasts and myofibroblasts. In addition to participating to the tumor tissue frame, these cells contribute actively to tumor nutrition and progression through neo-angiogenesis and production of a variety of molecules including numerous proteases, of which a number (MMP14, MMP11, FAP and uPA) are almost exclusively produced by reactive stromal cells. Cancer cells interact with reactive stromal cells which involves a large number of proteases. Several molecules (TGFbeta, PDGF, EMMPRIN) produced by cancer cells induce the production of stromal proteases which in turn stimulate cancer cells through binding to a receptor (for example, MMP-2 and integrin alpha v beta 3). Our experience shows that protease overexpression by reactive stromal cells (cathepsin D, MMP-11, MMP-14) leads to an adverse clinical course in breast cancer. Phenotypic and genotypic differences were found between reactive stromal cells and fibroblasts of normal tissue and our research team found that reactive stromal cells also respond differently to similar stimulations in different individuals. These results support the hypothesis that the biologic behaviour of cancer is not only dependent on tumour characteristics but also on those of patients'stromal cells and that comparable tumours in two individuals may follow different clinical courses. These studies and our experience underscores the importance of characterising cancer-associated reactive stromal cells because of the therapeutic potential of this approach. Furthermore, reactive stromal cells should be genetically more stable that cancer cells and, in theory, should less likely develop mutations and treatment resistance.
 ...
PMID:[Proteases by reactive stromal cells in cancer: an attractive therapeutic target]. 1698 Feb 37

Tobacco smoking is an important risk factor for the development of severe periodontitis. Recently, we showed that nicotine affected mineralized nodule formation, and that nicotine and lipopolysaccharide stimulated the formation of osteoclast-like cells by increasing production of macrophage colony-stimulating factor (M-CSF) and prostaglandin E2 (PGE2) by human osteoblastic Saos-2 cells. In the present study, we examined the effects of nicotine on the expression of matrix metalloproteinases (MMPs), tissue inhibitors of matrix metalloproteinases (TIMPs), the plasminogen activation system including the component of tissue-type plasminogen activator (tPA), urokinase-type PA (uPA), and PA inhibitor type 1 (PAI-1), alpha7 nicotine receptor, and c-fos. We also examined the effect of the nicotine antagonist D-tubocurarine on nicotine-induced expression of MMP-1. Gene expression was examined using real-time polymerase chain reaction (PCR) to estimate mRNA levels. In addition, expression of the MMP, TIMP, uPA, tPA, and PAI-1 proteins was determined by Western blotting analysis. Nicotine treatment caused expression of MMP-1, 2, 3, and 13, but not MMP-14, to increase significantly after 5 or 10 d of culture; MMP-14 expression did not change through day 14. Enhancement of MMP-1 expression by nicotine treatment was eliminated by simultaneous treatment with D-tubocurarine. In the presence of nicotine, expression of uPA, PAI-1, or TIMP-1, 2, 3, or 4 did not change over 14 d of culture, whereas expression of tPA increased significantly by day 7. Nicotine also increased expression of the alpha7 nicotine receptor and c-fos genes. These results suggest that nicotine stimulates bone matrix turnover by increasing production of tPA and MMP-1, 2, 3, and 13, thereby tipping the balance between bone matrix formation and resorption toward the latter process.
 ...
PMID:Nicotine treatment induces expression of matrix metalloproteinases in human osteoblastic Saos-2 cells. 1715 81

The present study investigated the role of integrin-linked kinase (ILK) in TGFbeta1-stimulated invasion/migration of human ovarian cancer cells. We investigated TGFbeta1 regulation of ILK, and effects of ILK knockdown on TGFbeta1-stimulated invasion/migration and the associated proteinase systems, urokinase plasminogen activator (uPA) and matrix metalloproteinases (MMPs) in SKOV3 cells. TGFbeta1 stimulated ILK kinase activity, and had no effect on ILK protein/mRNA levels. Transient transfection of an ILK-specific siRNA (ILK-H) reduced ILK protein level, mRNA level and kinase activity. ILK knockdown by ILK-H suppressed the basal and TGFbeta1-stimulated invasion and migration. Further, ILK-H reduced the basal and TGFbeta1-stimulated secretion of uPA, and increased the secretion of its inhibitor (PAI-1). Conversely, ILK-H did not affect TGFbeta1-stimulated secretion of MMP2 and its cell-associated activator MT1-MMP. Additionally, TGFbeta1 activated Smad2 phosphorylation, and this was not affected by ILK knockdown. Earlier reports indicate that Smad2 activation increased the expression of MMP2 and MT1-MMP. Thus, TGFbeta1 may act through ILK-independent and Smad2-dependent signaling in regulating MMP2 and MT1-MMP in SKOV3 cells. Collectively, this study suggests that ILK serves as a key mediator in TGFbeta1 regulation of uPA/PAI-1 system critical for the invasiveness of human ovarian cancer cells. And ILK is a potential target for cancer therapy.
 ...
PMID:Critical involvement of ILK in TGFbeta1-stimulated invasion/migration of human ovarian cancer cells is associated with urokinase plasminogen activator system. 1718 79

In degrading the extracellular matrix, matrix metalloproteinases (MMP) and the plasminogen activator (PA) system may play a critical role in extensive remodeling that occurs in the bovine mammary gland during development, lactation, and involution. Therefore, the aim of our study was to investigate the mRNA expression of MMP-1, MMP-2, MMP-14, MMP-19, tissue inhibitor of metalloproteinases (TIMP)-1, TIMP-2, urokinase-type PA, tissue-type PA, urokinase-type PA receptor, and PA inhibitor-1 by quantitative PCR and to localize with immunohistochemistry MMP-1, MMP-2, MMP-14, and TIMP-2 proteins in the bovine mammary gland during pubertal mammogenesis, lactogenesis, galactopoiesis, and involution. Expression of mRNA for each of the studied factors was relatively lower during galactopoiesis and early involution but was markedly increased during mammogenesis and late involution, 2 stages in which tissue remodeling is especially pronounced. The localization of proteins for MMP-1, MMP-14, and TIMP-2 showed a similar trend with strong staining intensity in cytoplasm of mammary duct and alveolar epithelial cells during pubertal mammogenesis and late involution. Interestingly, MMP-2 protein was localized only in the cytoplasm of endothelial cells during late involution. Our study demonstrated clearly that expression of extracellular matrix-degrading proteinases coincides with a concomitant expression of their inhibitors. High expression levels of MMP, TIMP, and PA family members seem to be a typical feature of the nonlactating mammary gland.
 ...
PMID:Expression and localization of extracellular matrix-degrading proteinases and their inhibitors in the bovine mammary gland during development, function, and involution. 1723 51

The corpus luteum (CL) offers the opportunity to study high proliferative processes during its development and degradation processes during its regression. We examined the mRNA expression of matrix metalloproteases (MMP)-1, MMP-2, MMP-9, MMP-14, MMP-19, tissue inhibitor of MMP (TIMP)-1, TIMP-2, tissue plasminogen activator (tPA), urokinase plasminogen activator (uPA), uPA-receptor (uPAR), PA-inhibitors (PAI)-1, PAI-2 in follicles 20 h after GnRH application, CLs during days 1-2, 3-4, 5-7 and 8-12 of the oestrous cycle as well as after induced luteolysis. Cows in the mid-luteal phase were injected with Cloprostenol and the CLs were collected at 0.5, 2, 4, 12, 24, 48 and 64 h after PGF2alpha injection. Real-time RT-PCR determined mRNA expressions. Expression from 20 h after GnRH to day 12: MMP-1, MMP-2, MMP-14 and tPA showed a clear expression, but no regulation. TIMP-1 and uPAR mRNA increased when compared with the follicular phase. TIMP-2, MMP-9, MMP-19 and uPA increased from the follicular phase to days 8-12. PAI-1 and PAI-2 expression increased from days 1-7 and decreased to days 8-12. Induced luteolysis: MMP-1, MMP-2, MMP-9, MMP-14, MMP-19 and TIMP-1 all increased at different time points and intensities, whereas TIMP-2 was constantly decreased from 24 to 64 h. The plasminogen activator system and their inhibitors were up-regulated from 2 to 64 h, tPA was already increased after 0.5 h. Immunohistochemistry for MMP-1, MMP-2, MMP-14: an increased staining for MMP-1 and MMP-14 was seen in large luteal cells beginning 24 h after PGF2alpha application. MMP-2 showed a strong increase in staining in endothelial cells at 48 h.
 ...
PMID:Expression and localisation of extracellular matrix degrading proteases and their inhibitors during the oestrous cycle and after induced luteolysis in the bovine corpus luteum. 1770 71

Matrix metalloproteinases (MMPs) play a critical role in tumor development and invasion. The aim of this study is to elucidate peculiarity of expression of interstitial collagenase (MMP-1) and its endogenous regulators in the process of oncogenic transformation of fibroblasts by E7 gene of HPV16. Papilloma virus type 16 and 18 are aetiological factor of cervical cancer. We have studied expression of MTI-MMP, MMP-1, tissue inhibitor of these proteases TIMP-1 and urokinase-typeplasminogen activator (uAP). The study was carried out using fibroblasts immortalized by LT gene (IF) and transformed by E7 gene of HPV-16 fibroblasts (TF). Primary culture of Fisher rat embryo fibroblasts was used as a control (PF). mRNA expression was studied by RT-PCR, enzymatic activity--by hydrolysis of fluorogenic type I collagen. It was found that cell transformation is accompanied by: a) 2-3 fold induction of MT1-MMP mRNA expression (vs PF); b) the decrease in mRNA level of TIMP-1 (1,5-2 fold); c) unchanged uPA expression. Cell immortalization is accompanied by: a) the increase of MT1-MMP expression (1,5-2 fold); b) unchanged TIMP-1 expression; c) the increase of uPA expression (2-4 fold) (vs PF and TF). MMP secreted activity and activity in lysates of TF increased but the level of free endogenous MMP inhibitors decreased (vs IF). Data on gene expression are consistent with enzymatic data on the collagenolytic activity. These results suggest changes in enzyme/inhibitor/activator ratio both TF and IF and significant enhancement of the destructive potential of the TF.
 ...
PMID:[Expression of interstitial collagenase and its endogenous regulators in immortalized and transformed by E7 gene HPV16 fibroblasts]. 1772 83

Proteolysis is essential for decidual development during embryonic implantation, but little is known regarding the expression and functions of membrane-type matrix metalloproteinases (MT-MMPs) and urokinase-type plasminogen activator (uPA) and its receptor uPAR in decidua. Therefore, their protein and mRNA levels were analysed in three first trimester decidual tissues, decidual secretory endometrium (DSE), decidua parietalis (DP) and basalis (DB). Decidua was obtained during first trimester pregnancy termination. uPA, uPAR, and MT1/2/3/5-MMP expression were studied by RT-PCR and immunohistochemistry, and CD56-positive uNK cells and CD68-positive macrophages were quantified in serial sections. The mRNAs and antigens of all proteases and uPAR were detectable in the decidual tissues and extravillous trophoblasts (EVT). mRNA levels of all proteases and uPAR, except MT5-MMP, were elevated in both DB and DP compared to DSE, being significant for MT1-MMP and uPAR in DP. MT2- and MT3-MMP mRNAs in DB were 24- and 10-fold higher than in DSE, and 19- and 7-fold increased compared to DP. At the protein level uPA and uPAR were particularly elevated in DB, while pro-angiogenic MT1- and MT3-MMPs were elevated in both DB and DP compared to DSE. MT2-MMP was prominently present in all conditions. The number of uNK cells was increased in DB and DP versus DSE, while a comparable increase in macrophages did not reach statistical significance. These data are consistent with a differential regulation of pericellular proteases in decidua by pregnancy-induced hormones, immune cells and EVT.
 ...
PMID:Pericellular-acting proteases in human first trimester decidua. 1817 89

The aim of the present study was to evaluate the pattern of regulation of vascular endothelial growth factor (VEGF)-A (isoforms 121, 165, 189), VEGF receptor tyrosine kinases (VEGF-R1 and VEGF-R2), matrix metalloproteinase (MMP)-1, MMP-2, MMP-14, MMP-19, tissue-specific inhibitor of metalloproteinases (TIMP)-1, TIMP-2, tissue plasminogen activator (tPA), urokinase plasminogen activator (uPA), urokinase plasminogen activator receptor (uPAR) and plasminogen activator inhibitor-1 (PAI-1) in time-defined follicle classes before (0 h) and after the application of gonadotrophin-releasing hormone (GnRH). Bovine ovaries containing periovulatory follicles or new corpora lutea (CL; Days 1-2) were collected 0, 4, 10, 20 and 25 h (follicles) or 60 h (CL) after the injection of GnRH. Transcripts of VEGF isoforms (VEGF(121), VEGF(165), VEGF(189)) were upregulated 4 h after GnRH injection (during the luteinising hormone (LH) surge) and decreased thereafter to lowest levels around ovulation. All VEGF isoforms and their receptors were upregulated again after ovulation. The VEGF peptide concentration in follicular fluid decreased 20 h after GnRH injection, followed by an increase in follicles 25 h after GnRH. Expression of MMP-1 mRNA increased rapidly 4 h after GnRH injection and remained high during the entire experimental period. In contrast, MMP-19 mRNA increased significantly only after ovulation. Expression of TIMP-1 mRNA increased 4 h after GnRH and again after ovulation. Expression of tPA mRNA increased 4 h after GnRH and remained high during the entire experimental period, whereas expression of uPA transcripts increased significantly only after ovulation. Both uPAR and PAI-1 mRNA levels increased in follicles 4 h after GnRH and again after ovulation. The amount of MMP-1 protein (immunolocalisation) increased in follicles 10 h after GnRH: additional staining was observed in the granulosa cell layer. In conclusion, the temporal and spatial pattern of regulation of VEGF and extracellular matrix-degrading proteinases during periovulation suggests they are important mediators of the LH-dependent rupture of bovine follicles and for early CL formation (angiogenesis).
 ...
PMID:Effect of the luteinising hormone surge on regulation of vascular endothelial growth factor and extracellular matrix-degrading proteinases and their inhibitors in bovine follicles. 1825 15

Localization of proteases to the surface of endothelial cells and remodeling of the extracellular matrix (ECM) are essential to endothelial cell tube formation and angiogenesis. Here, we partially localized active cathepsin B and its cell surface binding partners, S100A/p11 (p11) of the annexin II heterotetramer (AIIt), to caveolae of human umbilical vein endothelial cells (HUVEC). Via a live-cell proteolysis assay, we observed that degradation products of quenched-fluorescent (DQ)-proteins (i.e. gelatin and collagen IV) colocalized intracellularly with caveolin-1 (cav-1) of HUVEC grown in either monolayer cultures or in vitro tube formation assays. Activity-based probes that bind covalently to active cysteine cathepsins and degradation products of DQ-collagen IV partially localized to intracellular vesicles that contained cav-1 and active cysteine cathepsins. Biochemical analyses revealed that the distribution of active cathepsin B in caveolar fractions increased during in vitro tube formation. Pro-uPA, uPAR, MMP-2 and MMP-14, which have been linked with cathepsin B to ECM degradation pathways, were also found to increase in caveolar fractions during in vitro tube formation. Our findings are the first to demonstrate through live-cell imaging ECM degradation in association with active cathepsin B in caveolae of endothelial cells during tube formation.
 ...
PMID:Live-cell imaging demonstrates extracellular matrix degradation in association with active cathepsin B in caveolae of endothelial cells during tube formation. 1933 19

We previously demonstrated that the CNYYSNS peptide derived from tumstatin inhibited in vivo tumor progression. The YSNS motif formed a beta-turn crucial for biological activity. More recently, a YSNSG cyclopeptide with a constrained beta-turn on the YSNS residues was designed. Intraperitoneal administration of the YSNSG cyclopeptide inhibited in vivo melanoma progression more efficiently than the native linear peptide. In the present article, we showed that the YSNSG cyclopeptide also triggered an inhibition of in vivo tumor neovascularization and we further analyzed its in vitroantiangiogenic effect. The YSNSG cyclopeptide did not alter endothelial cell proliferation but inhibited cell migration by 83% in an in vitro wound healing model. The inhibition was mediated by a decrease in active MT1-MMP at the migration front as well as a decrease in u-PA and u-PAR expression. The cyclopeptide also altered beta1-integrin distribution in endothelial cell lamellipodia, induced a strong decrease in the phosphorylated focal adhesion kinase (p125(FAK)), disorganized F-actin stress fibers and decreased the number of lamellipodia, resulting in a non migratory phenotype. Our results confirm the YSNSG cyclopeptide as a potent antitumor agent, through both the inhibition of invasive properties of tumor cells and the antiangiogenic activity.
 ...
PMID:The YSNSG cyclopeptide derived from tumstatin inhibits tumor angiogenesis by down-regulating endothelial cell migration. 1955 65


<< Previous 1 2 3 4 5 Next >>