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)

Left ventricular (LV) remodeling following myocardial infarction (MI) is a complex process involving extracellular matrix degradation and fibrosis. While early remodeling is beneficial, chronic remodeling leads to decompensated heart failure (HF). We assessed the hypothesis that activation of the plasminogen-MMP system is involved in the remodeling of the infarct scar and compared it to the remaining viable myocardium. MI was induced by coronary artery ligature in 42 male Wistar rats. Three months following surgery, animals were divided into compensated (n=26) or decompensated (n=16) groups and compared to sham-operated rats (n=17). Scar and remaining viable LV myocardium (LVM) were separately analyzed for MMP-2, -7, -9, urokinase type and tissue type plasminogen activator (uPA and tPA) mRNA levels by RT-PCR. Their protein or activity levels, plus those of plasminogen/plasmin, tissue inhibitor of metalloproteinase-1, -2, -4 (TIMP-1, -2, -4) and plasminogen activator inhibitor-1 (PAI-1) were analyzed in tissue conditioned media by Western blot, ELISA and/or zymography. MMP and plasmin proteolytic activities were increased in the scar as compared to paired LVM thus indicating that activation of plasminogen and pro-MMPs is a key event in scar tissue remodeling. MMP and plasminogen activators (uPA, tPA) mRNAs were increased accordingly. Furthermore, inhibitors of the proteolytic enzymes, TIMP-1 and PAI-1 were increased in the scars from failing hearts and LVM thus suggesting a dynamic interplay between proteolysis and its inhibitors. This study shows a high degree of activation of the MMP-plasminogen system and the balance with their inhibitors in the infarcted myocardium, and suggests that this activation participates more to the remodeling of the scar tissue than to the remaining myocardium.
 ...
PMID:The plasminogen-MMP system is more activated in the scar than in viable myocardium 3 months post-MI in the rat. 1562 36

The aim of this study was to assess the expression of several metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in exudative pleural effusions, and their relationship with inflammatory and fibrinolytic mediators in parapneumonic effusions. The study included 51 parapneumonic effusions (30 empyema or complicated parapneumonic, 21 noncomplicated parapneumonic), 28 tuberculous, 30 malignant and 30 transudates. Inflammatory markers (tumour necrosis factor-alpha, interleukin-8, polymorphonuclear elastase), fibrinolytic system variables (tissue plasminogen activator (PA), urokinase PA (u-PA), plasminogen activation inhibitor (PAI)-1, PAI-2), and several MMPs (MMP-1, MMP-2, MMP-8, MMP-9) and TIMPs (TIMP-1, TIMP-2) were determined by ELISA in plasma and pleural fluid. Elevated MMP-2 and TIMP-1 concentrations were observed in all the pleural fluid samples studied. The group of empyema or complicated parapneumonic effusions showed higher MMP-1, MMP-8 and MMP-9 concentrations than the remaining exudates. There was no correlation between MMP and TIMP levels in plasma and pleural fluid in this group of effusions. In parapneumonic effusions, MMP-1, MMP-8 and MMP-9 showed a positive correlation with the inflammatory markers and with u-PA and PAI-1. Moreover, there was a relationship between MMP-8 concentration in pleural fluid and pleural thickening at the end of treatment. In conclusion, elevated metalloproteinase-1, -8 and -9 expression was found in parapneumonic pleural effusions. These metalloproteinases could be implicated in the local inflammatory response existing in this group of effusions.
 ...
PMID:Metalloproteinases and tissue inhibitors of metalloproteinases in exudative pleural effusions. 1564 Mar 30

Rho GTPases are overexpressed in human tumors and are involved in a variety of cellular processes such as organization of the actin cytoskeleton, cell-cell contact and malignant transformation. EGFR activation plays a key role in the acquisition of motile properties in carcinoma cells, and it has been proposed that downregulation of FAK activity is one of its most relevant consequences. In the present study, using mammary MCF-7 cells, we demonstrated that overexpression of the active form of the small GTPase RhoA induced the activation of EGFR by a phenomenon that depends on the activity of a metalloproteinase (MMP), which presumably cleaves a membrane-bound EGFR ligand. The EGFR tyrosine phosphorylation correlates with ERK1,2 activation and the stimulation of urokinase production. An aggressive mammary cell line (MDA-MB-231) that overexpresses both RhoA and EGFR in their active forms also displayed an MMP-dependent activation mechanism of EGFR. RhoA-GTP-transfected cells showed a cortical array of F-actin, rounded morphology, reduced spreading potential and a dephosphorylation of FAK that was released by integrin-dependent fibronectin adhesion and a specific EGFR tyrosine kinase inhibitor. Our results suggest that the MMP-dependent EGFR activation observed in V14 RhoA cells represents the starting point of a signaling route that promotes cell motility by activation of ERK1,2 and further enhancement of proteases production.
 ...
PMID:Overexpression of RhoA-GTP induces activation of the Epidermal Growth Factor Receptor, dephosphorylation of focal adhesion kinase and increased motility in breast cancer cells. 1596 82

Pancreatic cancer is one of the most lethal tumours of the gastrointestinal tract. The ability to predict which patients would benefit most from surgical intervention and/or chemotherapy would be a great clinical asset. Considerable research has focused on identifying molecular events in pancreatic carcinogenesis, and their correlation with clinicopathological variables of pancreatic tumours and survival. This systematic review examined evidence from published manuscripts looking at molecular markers in pancreatic cancer and their correlation with tumour stage and grade, response to chemotherapy and long-term survival. A literature search was undertaken using PubMed and MEDLINE search engines, using the keywords p53, p21, p16, p27, SMAD4, K-ras, cyclin D1, Bax, Bcl-2, EGFR, EGF, c-erbB2, HB-EGF, TGFbeta, FGF, MMP, uPA, cathepsin, heparanase, E-cadherin, laminins, integrins, TMSF, CD44, cytokines, angiogenesis, VEGF, IL-8, beta-catenin, DNA microarray, and gene profiling. A bewildering number of biomarkers are currently under evaluation. For the most part, the evidence regarding their application as prognostic indicators is conflicting. The advent of gene microarray and mass spectrometric protein profiling offers the potential to examine many different biomarkers simultaneously. This 'protein/gene signature' could revolutionise work in this field and allow researchers to develop accurate and reproducible predictions of survival based on protein or gene profiles.
 ...
PMID:Molecular prognostic markers in pancreatic cancer: a systematic review. 1614 90

Liver fibrosis and cirrhosis involve multiple cellular and molecular events that lead to deposition of an excess of extracellular matrix proteins and increase the distortion of normal liver architecture. Etiologies include chronic viral hepatitis, alcohol abuse and drug toxicity. Degradation of these matrix proteins occurs predominantly as a result of a family of enzymes called metalloproteases (MMPs) that specifically degrade collagenous and non-collagenous substrates. Matrix degradation in the liver is due to the action of at least four of these enzymes: MMP-1, MMP-2, MMP-3 and MMP-9. In the fibrinolytic system, MMPs can be activated through proteolytic cleavage by the action of urokinase plasminogen activator; a second mechanism includes the same metalloproteases. This activity is regulated at many levels in the fibrinolytic system. The main regulator is the PAI-1. This molecule blocks the conversion of plasminogen into plasmin, and the MMP cannot be activated. At a second level, the inhibition is possible by binding to inhibitors called TIMP that can inhibit the proteolitic activity even when the MMPs had been previously activated by plasmin. During abnormal conditions, overexpression of these inhibitors is directed by the transforming growth factor-beta that in a fibrotic disease acts as an extremely important adverse factor.
 ...
PMID:[Hepatic fibrosis: role of matrix metalloproteases and TGFbeta]. 1616 29

Glioblastoma multiforme (GBM) is among the most treatment-refractory of all human tumors. Radiation is effective at prolonging survival of GBM patients; however, the vast majority of GBM patients demonstrate progression at or near the site of original treatment. We have identified primary GBM cell lines that demonstrate increased invasive potential upon radiation exposure. As this represents a novel mechanism by which radiation-treated GBMs can fail therapy, we further investigated the identity of downstream signaling molecules that enhance the invasive phenotype of irradiated GBMs. Matrigel matrices were used to compare the extent of invasion of irradiated vs. non-irradiated GBM cell lines UN3 and GM2. The in vitro invasive potential of these irradiated cells were characterized in the presence of both pharmacologic and dominant negative inhibitors of extracellular matrix and cell signaling molecules including MMP, uPA, IGFR, EGFR, PI-3K, AKT, and Rho kinase. The effect of radiation on the expression of these signaling molecules was determined with Western blot assays. Ultimately, the in vitro tumor invasion results were confirmed using an in vivo 9L GBM model in rats. Using the primary GBM cell lines UN3 and GM2, we found that radiation enhances the invasive potential of these cells via activation of EGFR and IGFR1. Our findings suggest that activation of Rho signaling via PI-3K is required for radiation-induced invasion, although not required for invasion under physiologic conditions. This report clearly demonstrates that radiation-mediated invasion is fundamentally distinct from invasion under normal cellular physiology and identifies potential therapeutic targets to overcome this phenomenon.
 ...
PMID:Radiation enhances the invasive potential of primary glioblastoma cells via activation of the Rho signaling pathway. 1620 Mar 46

Although it has been shown that the cross-talk between osteoblasts and tumor cells stimulates proliferation and invasion of prostate carcinoma (PCa) cells, the molecular mechanisms underlying this event are largely unknown. In this study, we demonstrated that the PCa cells, PC3, derived from bone metastasis, undergo changes of their invasive capability if grown in the presence of osteoblast-derived conditioned media (OBCM). Specifically, they were able to organize tridimensional structures in Matrigel, such as large branching colonies, tube-like structures and clusters of proliferating cells, after treatment. At the ultrastructural level, we observed that PC3 cells grown in the presence of OBCM presented an increment of membrane activity with a blast of shed membrane vesicles from the cell surface. After 6 h of incubation, protein content was approximately 5-fold more elevated in vesicles isolated from PC3 cells cultured in OBCM than in unstimulated cultures. Gelatin zymography of vesicles collected from OBCM-treated PC3 cells showed an increment of lytic bands of MMP family members identified as pro-enzymatic and active forms of gelatinase A (MMP-2) and gelatinase B (MMP-9). By casein-plasminogen zymography, this latter culture also presented an elevated level of high-molecular weight urokinase plasminogen activator (HMW-uPA). Purified vesicles from OBCM-treated PC3 cells incubated with Matrigel cleaved its components more efficiently than vesicles from untreated PC3 cells. Collectively, these findings indicate that osteoblasts produce factor/s able to modify the invasive capability of prostate cancer cells, increasing the amount of shed vesicles and of their associated lytic enzymes.
 ...
PMID:Osteoblast-conditioned media stimulate membrane vesicle shedding in prostate cancer cells. 1652 40

This study examined whether intraluminal thrombus in abdominal aortic aneurysms (AAAs) is a source of fibrinolytic activity and proteolysis that could weaken the aneurysm wall. Plasmin, tissue plasminogen activator (tPA), and urokinase plasminogen activator (uPA) activity, plasminogen activator inhibitor 1 (PAI-1), and alpha2-antiplasmin (alpha2AP) antigen were measured in the AAA wall and juxtamural and luminal aspects of intraluminal thrombus in 18 patients. The aneurysm wall contained 100-fold higher tPA activity (1.06 +/- 0.34 [standard error of measurement] U/mg soluble protein) compared with juxtamural thrombus (JMT) (0.011 +/- 0.001 ) and luminal thrombus (LT) (0.01 +/- 0.001) (p < .00001) and over 6-fold higher uPA activity (29.3 +/- 3.4 IU/mg compared with the JMT (4.3 +/- 2.4, p = .00024) and LT (7.9 +/- 1.76, p = .0005). The LT had significantly lower levels of PAI-1 (1.26 +/- 0.34 ng/mg) than the AAA wall (2.08 +/- 0.51, p = .04) and the JMT (3.94 +/- 0.85, p = .007). The levels of alpha2AP in the wall (19.4 +/- 3.1 ng/mg) were lower than in the JMT or LT (43.0 +/- 7.9 ng/mg, p = .013, and 47.6 +/- 6.0 ng/mg, p = .002, respectively). There was no significant difference, however, in plasmin activity among the AAA wall, JMT, and LT. There were significant amounts of latent gelatinase B (matrix metalloproteinase [MMP]-9) in the AAA, JMT, and LT. Mean levels of activated MMP-9 activity were similar in the AAA, JMT, and LT. Plasmin activation of MMPs at the interface between intraluminal thrombus and the aneurysm wall may enhance proteolysis and accelerate aneurysm expansion.
 ...
PMID:Intraluminal thrombus enhances proteolysis in abdominal aortic aneurysms. 1684 17

Extracellular matrix metalloproteinase inducer (EMMPRIN) is a membrane glycoprotein overexpressed in many cancer tissues and is known for its ability to stimulate MMP expression. In this work, we show that EMMPRIN is also a regulator of the urokinase-type plasminogen activation (uPA) system of serine proteases, thus participating to the increase of the overall proteolytic function of the cancer cells. Enhanced EMMPRIN expression in a tumorigenic breast epithelial cell line NS2T2A increased the levels of uPA, uPA receptor, and the uPA inhibitor plasminogen activator inhibitor-1 (PAI-1), as measured by quantitative reverse transcription-PCR, Western blot, and plasminogen-casein zymography. This response was down-regulated by either EMMPRIN small interfering RNA or a blocking antibody to EMMPRIN. EMMPRIN-containing purified membrane fraction from Chinese hamster ovary cells when added exogenously to NS2T2A cells induced a similar activation of the uPA/PAI-1 system. Additionally, overexpression of EMMPRIN in NS2T2A cells increased uPA levels in cocultured endothelial cells, showing a paracrine regulation loop involving a tumor-stroma interaction. EMMPRIN-expressing cells also exhibited enhanced invasive potential in vitro, and the use of amiloride (uPA inhibitor) and marimastat (MMP inhibitor) showed that the two proteolytic systems reduced alone and in combination the invasive potential mediated through EMMPRIN. These data show a novel regulatory pathway for uPA activity and suggest that EMMPRIN is involved in uPA dysregulation observed in cancer.
 ...
PMID:Extracellular matrix metalloproteinase inducer up-regulates the urokinase-type plasminogen activator system promoting tumor cell invasion. 1721 Jun 77

The remodelling of extracellular matrix and angiogenesis represent two essential processes for tumor growth and metastatic dissemination. These phenomena imply many interactions between tumor cells and host cells via action of various proteases including metalloproteinases (MMPs) whose activity is controlled by TIMPs and serine proteases (tissue type Plasminogen Activator (tPA), urokinase type Plasminogen Activator (uPA) and plasmin) inhibited in particular by PAI-1 (Plasminogen Activator Inhibitor- 1). Evolution of tumors depends on the joint action of these enzymes, as well as precise balance between these proteases and their physiological inhibitors. Proteases regulate the fate and activity of many proteins by controlling appropriate intra- or extracellular localization; shedding from cell surfaces ; activation or inactivation of proteases and other enzymes, cytokines, hormones or growth factors and exposure of cryptic neoproteins. Hence, proteases initiate, modulate and terminate a wide range of important cellular functions by processing bioactive molecules an thereby control essential biological processes, such as DNA replication, cell-cycle progression, cell proliferation, differentiation and migration, morphogenesis and tissue remodelling, neuronal outgrowth, haemostasis, wound healing, immunity, angiogenesis and apoptosis. Work completed has for objective to elucidate the specific part played by serine proteases and MMPS produced by the host cells in the processes of tumor growth and angiogenesis. By using an original model of transplantation of malignant murine keratinocytes (PDVA cell line) into deficient mice (-/-) and wild type mice (+/+), we showed the essential proteolytic role of PAI-1 produced by host cells in the tumor progression and angiogenesis. This mechanism of PAI-1 action was confirmed by using the model in vitro aorta rings. By using deficient mice for one or two MMPs combined (MMP-2, MMP-3, MMP-9, MMP-11, MMP-2&9, MMP3&9), we demonstrated that only the combined deficiency of MMP-2 and -9 showed an absence of tumor invasion and angiogenesis. These data suggest the existence of compensatory mechanisms of a MMP by another MMP or another proteolytic way. These phenomena of redundancy are to be known and detailed to elaborate in a near future, the development of specific inhibitors of MMPS.
 ...
PMID:[Roles of serine proteases and matrix metalloproteinases in tumor invasion and angiogenesis]. 1728 5


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>