Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Degradation of the extracellular matrix plays a crucial role in cancer invasion. This degradation is accomplished by the concerted action of several enzyme systems, including generation of the serine protease plasmin by the urokinase pathway of plasminogen activation, different types of collagenases and other metalloproteinases, and other extracellular enzymes. The degradative enzymes are involved also in tissue remodelling under non-malignant conditions, and the main difference appears to be that mechanisms which regulates these processes under normal conditions are defective in cancer. Specific inhibitors have been identified for most of the proteolytic enzymes, e.g. plasminogen activator inhibitors (PAI's) and tissue inhibitors of metalloproteinases (TIMP's). It has been contemplated that these inhibitors counteracted the proteolytic activity of the enzymes, thereby inhibiting extracellular tissue degradation which in turn should prevent tumor cell invasion. This review focuses on plasminogen inhibitor type 1 (PAI-1). It is described that PAI-1 is not produced by the epithelial cancer cell but by the stromal cells in the tumors, suggesting a concerted action between stroma and tumor cells in the processes controlling proteolysis in cancer. The specific localization of PAI-1 to the tumor stroma and in many cases to areas surrounding the tumor vessels has lead us to suggest that PAI-1 serves to protect the tumor stroma from the ongoing uPA-mediated proteolysis. This hypothesis is supported by recent clinical data showing increased levels of PAI-1 in metastases as compared to the primary tumor as well as data demonstrating that high levels of PAI-1 in tumor extracts from breast, lung, gastric and ovarian cancer is associated with a shorter overall survival.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Plasminogen activator inhibitor type 1 in cancer: therapeutic and prognostic implications. 766 68

It has been shown that some types of tumour cells produce activated transforming growth factor beta-1 (TGF-beta 1). However, the mechanism for the activation of TGF-beta 1 derived from tumour cells has not been fully elucidated. The present study was undertaken to characterise an activator of latent TGF-beta 1 secreted from a human gastric cancer cell line, KATO-III. Western blot analyses using antibodies for TGF-beta 1, latency associated peptide (LAP) and latent TGF-beta 1-binding protein (LTBP) revealed that, in the cell lysate of KATO-III, TGF-beta 1 protein was expressed as a small latent complex of TGF-beta 1 and LAP. This was also confirmed by a gel chromatographic analysis of the cell lysate obtained from KATO-III. A 2.5 kb transcript of TGF-beta 1 mRNA was detected in KATO-III cells by Northern blot analysis. A gel chromatographic analysis of the conditioned medium from KATO-III cells revealed, in addition to the active form of TGF-beta 1, a factor which activated latent TGF-beta 1 from NRK-49F cells at fractions near a molecular size of 65,000. This factor was inactivated by heat (100 degrees C), acidification, trypsin and serine protease inhibitors. TGF-beta 1 activity in KATO-III cell lysate was not detected in the untreated state, but potent TGF-beta 1 activity was detected after acid treatment. These results suggest that KATO-III releases not only a latent TGF-beta 1 complex but also a type of serine protease, different from plasmin, plasminogen activator, cathepsin D, endoglycosidase F or sialidase, which activates the latent TGF-beta 1 complex as effectively as acid treatment.
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PMID:Identification of a transforming growth factor beta-1 activator derived from a human gastric cancer cell line. 766 80

We investigated the effect of gonadotropins on protease that were suggested to be implicated in the invasive activity of the trophoblast. hCG levels ranging from 10 x 10(3) to 333 x 10(3) IU/L produced a dose-dependent inhibition of the in vitro globinolytic activity of the purified proteases trypsin, chymotrypsin, and urokinase, but failed to inhibit plasmin, collagenase, elastase, and tissue-type plasminogen activator. Likewise, FSH inhibited purified trypsin and urokinase, but not plasmin or tissue-type plasminogen activator. Culture medium conditioned with human trophoblast displayed serine protease and urokinase-like activities; exposure of the cultured trophoblast to exogenous hCG markedly suppressed serine protease and urokinase activities in the conditioned medium. A short treatment of the conditioned medium with trypsin abolished the hCG-mediated inhibition of urokinase activity. The present findings offer an explanation for earlier observations that hCG reduced collagenase activity in trophoblasts without affecting the level of collagenase-specific mRNA. The present results are also consistent with the concept that hCG, by its direct ability to inhibit certain serine proteases and urokinase in trophoblast, suppresses a protease-mediated conversion of procollagenase to active collagenase. The ability of hCG to prevent initiation of the collagenolytic cascade suggests that gonadotropins may regulate the transient invasive activity of the trophoblast.
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PMID:Gonadotropin-mediated inhibition of proteolytic enzymes produced by human trophoblast in culture. 768 89

Tissue-type plasminogen activator (t-PA) is a remarkably specific protease: the only known substrate of this enzyme in vivo is a single peptide bond (Arg560-Val561) within the proenzyme plasminogen. Part of the substrate specificity of t-PA is due to a ternary interaction between fibrin, t-PA and plasminogen which reduces the Km of t-PA for plasminogen by a factor of 440. However, even in the absence of fibrin, t-PA continues to hydrolyze plasminogen more rapidly than does trypsin, a homologous serine protease. We have measured the extent of the specificity of t-PA for plasminogen by assaying t-PA and trypsin toward substrates modeled after the peptide sequence in plasminogen surrounding Arg560-Val561. Surprisingly, t-PA hydrolyzes these substrates with kcat/Km values which are 28,000-210,000-fold lower than those obtained using trypsin. Both the high activity toward plasminogen and the low activity toward peptides are also exhibited by the isolated protease domain. This suggests that the protease domain, in spite of its high homology to the nonspecific enzyme trypsin, is inherently specific for recognition of one or more structural features displayed by native plasminogen.
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PMID:Substrate specificity of tissue type plasminogen activator. Characterization of the fibrin independent specificity of t-PA for plasminogen. 770 3

Urokinase plasminogen activator (uPA) is a serine protease involved in cancer invasion and metastasis. uPA mediates its action while attached to a membrane-bound receptor (uPAR). In this investigation we show that uPAR levels correlate with uPA levels in human breast cancers. uPAR levels, however, do not correlate with other components of the plasminogen activator system such as tissue-type plasminogen activator (t-PA), PAI-I or PAI-2. In addition, uPAR levels showed no correlation with tumor size, axillary-node status or estrogen-receptor status. On the basis of an optimum cut-off point, patients with breast cancers containing high levels of uPAR had a worse prognosis than patients with low levels of the receptor. However, as a prognostic marker in breast cancer, uPAR was not as strong as uPA. Our results are consistent with data from model systems suggesting that both uPA and uPAR are necessary for metastasis.
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PMID:Urokinase plasminogen activator and urokinase plasminogen activator receptor in breast cancer. 776 29

We have developed a model whereby the middle cerebral artery in an experimental animal can be occluded by a photochemical reaction between rose bengal and green light. This causes endothelial injury followed by platelet adhesion, aggregation and formation of a platelet-rich thrombus at the site of the photochemical reaction. SUN9216, a modified tissue-type plasminogen activator, is a new thrombolytic agent which consists of the fibrin kringle 1 domain of plasminogen and the two kringles, the serine protease domains of the native tissue-type plasminogen activator. The mannose glycosylation site on the kringle 1 of tissue-type plasminogen activator is modified to yield a compound with a longer half-life in the blood than native tissue-type plasminogen activator. We evaluated the thrombolytic effects of recombinant tissue-type plasminogen activator and SUN9216 in the thrombotically occluded rat middle cerebral artery. SUN9216 was administered by continuous infusion or as a single bolus injection 30 min after the middle cerebral artery had been occluded by a thrombus. Both SUN9216 and recombinant tissue-type plasminogen activator caused reopening of the middle cerebral artery by thrombolysis. The efficacy of SUN9216 was higher than that of recombinant tissue-type plasminogen activator. Further, the area of ischaemic cerebral damage caused by the middle cerebral artery occlusion was significantly (P < 0.05) reduced by SUN9216, but in this respect, recombinant tissue-type plasminogen activator was ineffective.
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PMID:Thrombolytic efficacy of a modified tissue-type plasminogen activator, SUN9216, in the rat middle cerebral artery thrombosis model. 781 75

Plasminogen activator inhibitor 1 (PAI-1), the primary physiological inhibitor of t-PA, is an unusual member of the serpin family of serine protease inhibitors, in that it spontaneously converts to a latent form. Latent PAI-1 has been reported to share characteristics with the cleaved form of other serpins. Here we examine the conformation of four forms of PAI-1, active and latent wild-type, together with a noninhibitory, substrate mutant that is cleavable at P1-P1', and its cleaved product. The circular dichroism spectra of active and latent PAI-1 showed differences consistent with decreased alpha-helix from 26% to 22% and increased beta-sheet from 23% to 34% as active-->latent. Active and substrate PAI-1 were less thermostable than latent PAI-1, which was 50% denatured at 70 degrees C. In contrast, cleaved PAI-1 was very stable, with little loss of structure at 100 degrees C. Cleaved PAI-1 was much more resistant to guanidinium chloride (Gdn-HCl), 50% unfolding requiring 4.5 M Gdn-HCl, while active, latent, and substrate forms of PAI-1 were 50% unfolded in 2-2.5 M Gdn-HCl. The differences in fluorescence emission maxima, latent 339 nm, active 336 nm, substrate 343 nm, and cleaved 333 nm, underline the contrast between latent and cleaved PAI-1. The conformational changes occurring on cleavage are clearly more profound than those seen on transition from active to latent PAI-1.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Conformational studies on plasminogen activator inhibitor (PAI-1) in active, latent, substrate, and cleaved forms. 782 21

Human hepatocyte growth factor (hHGF) has considerable sequence homology with plasminogen and both proteins can be activated by plasminogen activators. The aim of this study was to investigate the relationship between plasma hHGF and fibrinolysis in patients with fulminant hepatic failure (FHF), in whom proteases of coagulation are known to be activated and hHGF levels have been shown to be raised as a consequence of hepatic regeneration. Serum hHGF measured by ELISA was increased in FHF (median 6.67 ng/ml, range 1.2-62 ng/ml), but the values did not correlate with the decreased plasminogen level (median 9%., range 0.7-35.5%) or the level of t-PA which was normal. There was a significant correlation between serum hHGF and increased plasma D-dimer (median 2,163 microgram/l, range 39-7 311 microgram/l), produced by the action of plasmin on fibrin and increased plasma thrombin-antithrombin III complexes (TAT, median 31.7 microgram/l, range 3.7-105 microgram/l). These relationship could be indicative of an involvement of blood coagulation, possibly a specific serine protease, in hHGF activity. After liver transplantation, plasma hHGF was rapidly cleared to almost normal levels, whereas D-dimer and TAT continued to be at elevated levels.
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PMID:Hepatocyte growth factor and plasminogen activation in fulminant hepatic failure. 784 6

Rabbits were repeatedly immunized with a chimeric plasminogen activator composed of the kringle-2 domain of human tissue-type plasminogen activator (t-PA) attached to the serine protease domain of the human urokinase-type plasminogen activator (u-PA). IgG from these rabbits was purified, biotinylated and subjected to affinity chromatography on K2tu-PA covalently attached to Sepharose. Roughly half the antibodies recovered from the K2tu-PA column could subsequently be bound to a column with similarly immobilized t-PA, whereas the other half bound to a u-PA column. Less than 0.01% of the biotinylated anti-K2tu-PA antibodies did not bind to either t-PA or u-PA and perhaps are directed against neoantigenic determinants on K2tu-PA, not present in the natural plasminogen activators.
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PMID:Immunogenicity of the chimeric plasminogen activator K2tu-PA in rabbits. 789 28

In isolation human plasminogen possesses no enzymatic activity, yet upon formation of an equimolar complex with the bacterial protein streptokinase, it acquires a plasminogen activator function. The region(s) of plasminogen and of streptokinase which mediate complex formation has (have) not been previously published. Here it is reported that a single-residue substitution (Arg719-->Glu) in the serine protease domain of full-length Glu-plasminogen substantially reduces its affinity for streptokinase. The plasminogen variant displays no other significant differences from the wild-type molecule with respect to activation by two-chain urokinase-type plasminogen activator, recognition by monoclonal antibodies, or ability to undergo conformational change. It is concluded that Arg719 in human plasminogen is an important determinant of the streptokinase binding site, although further sites are likely to contribute both to the affinity of plasminogen for streptokinase and to mechanisms by which the active site is formed within the complex.
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PMID:Substitution of arginine 719 for glutamic acid in human plasminogen substantially reduces its affinity for streptokinase. 791 23


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