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)

Human promyelocytic HL-60 cells have been used as a model of acute leukemia to investigate the expression and the regulation of matrix metalloproteases (MMPs), known to contribute to the degradation of extracellular matrix components. As shown by gelatin zymography, HL-60 cells constitutively released significant amounts of proMMP-9 (92 kDa) and moderate amounts of proMMP-2 (72 kDa). Furthermore, casein zymography confirmed the presence of serine proteases in the form of pro-urokinase. Activation of proMMP-9 was dependent on the plasminogen activator/plasmin (PA/plasmin) system and was inhibited by aprotinin. MMP-9 was only detected in cellular extracts or conditioned media incubated with HL-60 cells, indicating that cells are essential to the activation process. Addition of plasminogen increased by 3-fold the basal invasive rate of these cells across a matrigel layer (2.1% versus 0.7% in control cells after 4 h of incubation). Taken together, these results indicate that HL-60 cells exhibit an autocrine activation mechanism of proMMP-9 via the PA/plasmin system and that activation of proMMP-9 increases their invasive potential.
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PMID:Production and activation of matrix metalloprotease-9 (MMP-9) by HL-60 promyelocytic leukemia cells. 932 78

The proteasome is a cytoplasmic high-molecular-weight structure composed of several smaller protein and RNA subunits. It has been associated with non-lysosomal pathways of intracellular degradation, expressing multicatalytic proteinase activities and specific RNase activity. By standard methods, we have isolated andpartially purified proteasomes from human epidermis. We obtained the expected multiple 24-32 kDa subunits by SDS-PAGE, and evidence of RNA. Proteasomes degraded casein, as well as chromogens for t-PA and trypsin but not for chymotrypsin, these proteolytic activities overlap, but do not coincide with those observed in other organs. We found that human epidermal 28 S and 18 S rRNAs were degraded, but yeast RNA was not. By means of zymography, we demonstrated, for the first time, that RNase activity persists after dissociation of the proteasome on the gel and that it co-localizes to the same range of molecular weight subunits as the proteinase activity.
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PMID:Proteasomal RNase activity in human epidermis. 962 96

Urokinase-type plasminogen activator (u-PA) and tissue-type plasminogen activator (t-PA) play important roles in fibrinolysis, cell migration, tissue destruction, angiogenesis and tissue remodeling. u-PA and t-PA activity in tissue are tightly regulated by plasminogen activator inhibitor-1 (PAI-1). However, little is known of the activity of endogenous plasminogen activators (PAs) and PAI-1 in ischemic brain. To evaluate whether cerebral ischemic injury induces endogenous PAs and PAI-1, we measured PA activity from brain homogenates, and examined the expression of t-PA mRNA, u-PA mRNA and PAI-1 mRNA from brain homogenates in C57BL/6J mice (n=45) weighing 29-35 g in which the middle cerebral artery (MCA) was occluded by a fibrin-rich clot. Brain homogenates were prepared for direct casein zymography from control non-ischemic mice (n=4) and mice at 2 h (n=5), 4 h (n=5), and 24 h (n=4) after MCA occlusion (MCAO). Also, u-PA and t-PA knockout mice at 4 h (n=2, each) after MCAO were used as a negative control for direct casein zymography. Frozen sections for in situ zymography were obtained from control mice (n=2) and mice at 2 h, 4 h, and 24 h (n=2, per time point) after clot occlusion. Brain homogenates were prepared for reverse transcriptase-polymerase chain reaction (RT-PCR) to examine t-PA mRNA, u-PA mRNA and PAI-1 mRNA expression from control non-ischemic mice (n=4) and mice at 2 h (n=5), 4 h (n=5), and 24 h (n=5) after MCAO. By direct casein zymography, u-PA activity increased at 4 h (P<0.05), and 24 h (P<0.05) after stroke in the ischemic hemisphere compared with the non-ischemic mice. Activity of t-PA in ischemic brain was not significantly different from the control group. As measured by in situ zymography, PA activity, most likely u-PA, was present in the ischemic hemisphere. By RT-PCR, expression of PAI-1 mRNA, but not u-PA mRNA and t-PA mRNA, increased 3-, 15- and 25-folds in the ischemic hemisphere at 2 h, 4 h and 24 h after stroke, respectively, compared with control mice. This study demonstrates that PAI-1 mRNA and u-PA activity increase in mouse brain after stroke.
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PMID:Endogenous plasminogen activator expression after embolic focal cerebral ischemia in mice. 1043 99

The expression of plasminogen and plasminogen activators (PG/PAs) in reactive astrocytes was examined following scratch injury. In response to injury, casein-degrading activity could be observed around astrocytes. The protein expression of tissue-type plasminogen activator (tPA) was up-regulated, while the free form of urokinase-type plasminogen activator (uPA) was not detected. Consistent with these findings, results obtained with zymograph assay also revealed that tPA activity, but not uPA activity, was up-regulated. Moreover, the addition of 6-amino-caproitic acid (EACA) to casein-covered astrocytes significantly prevented the recovery of the injured astrocytes in a dose-dependent manner. Taken together, our data demonstrate that the expression of PG/PAs in cultured astrocytes is regulated following injury, suggesting that caseinolytic activity is an essential component during the process of astrocyte recovery.
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PMID:Altered expression of tissue-type plasminogen activator and type 1 inhibitor in astrocytes of mouse cortex following scratch injury in culture. 1079 47

R.E. Hill and S.P. Mackessy. Characterization of venom (Duvernoy's secretion) from twelve species of colubrid snakes and partial sequence of four venom proteins. Toxicon XX, xx-yy, 2000. - Venomous colubrids, which include more than 700 snake species worldwide, represent a vast potential source of novel biological compounds. The present study characterized venom (Duvernoy's gland secretion) collected from twelve species of opisthoglyphous (rear-fanged) colubrid snakes, an extremely diverse assemblage of non-venomous to highly venomous snakes. Most venoms displayed proteolytic activity (casein), though activity levels varied considerably. Low phosphodiesterase activity was detected in several venoms (Amphiesma stolata, Diadophis punctatus, Heterodon nasicus kennerlyi, H. n. nasicus and Thamnophis elegans vagrans), and acetylcholinesterase was found in Boiga irregularis saliva and venom, but no venoms displayed hyaluronidase, thrombin-like or kallikrein-like activities. High phospholipase A(2) (PLA(2)) activity was found in Trimorphodon biscutatus lambda venom, and moderate levels were detected in Boiga dendrophila and D. p. regalis venoms as well as B. dendrophila and H. n. nasicus salivas. Non-reducing SDS-PAGE revealed 7-20 protein bands (3.5 to over 200 kD, depending on species) for all venoms analyzed, and electrophoretic profiles of venoms were typically quite distinct from saliva profiles. Components from A. stolata, Hydrodynastes gigas, Tantilla nigriceps and T. e. vagrans venoms showed protease activity when run on gelatin zymogram gels. N-terminal protein sequences for three 26 kD venom components of three species (H. gigas, H. torquata, T. biscutatus) and one 3.5 kD component (T. nigriceps) were also obtained, and the 3.5 kD peptide showed apparent sequence homology with human vascular endothelial growth factor; these data represent the first sequences of colubrid venom components. Protease, phosphodiesterase and PLA(2) activities are also common to elapid and viperid snake venoms, but it is apparent that numerous other (as yet undescribed) components make up the majority of colubrid venom proteins. The complex nature of venoms produced by most species surveyed, and the high levels of protease or phospholipase A(2) activity of some venoms, suggest that many colubrids could become an important source of human health concern as encounters with these snakes increase.
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PMID:Characterization of venom (Duvernoy's secretion) from twelve species of colubrid snakes and partial sequence of four venom proteins. 1085 9

This study aims to investigate the mechanism by which prolactin and GH interact to maintain mammary epithelial cell function in the rat. IGF-I is an important survival factor for the mammary gland and we have demonstrated that the effects of GH and prolactin involve IGF-I. GH acts by increasing IGF-I whilst prolactin acts by inhibiting the expression of IGFBP-5 from the mammary epithelium. During mammary involution, when serum prolactin levels decline, IGFBP-5 expression is dramatically upregulated and it binds with high affinity to IGF-I preventing IGF-I interaction with the IGF-receptor and thus leading to epithelial cell apoptosis. We have identified a specific interaction of IGFBP-5 with alpha s2-casein. This milk protein has also been shown to bind plasminogen and its activator tissue-type plasminogen activator (tPA) leading to enhanced conversion of plasminogen to plasmin. Plasmin is an important initiator of re-modelling of the extracellular matrix during mammary involution. A potential interaction between the cell death and extracellular matrix remodelling is evident from the observation that IGFBP-5 binds to plasminogen activator inhibitor-I (PAI-1). We thus hypothesized that IGFBP-5 could activate cell death by sequestration of IGF-I and activate plasminogen cleavage by sequestering PAI-1. In support of this hypothesis we have shown that both prolactin and GH inhibit tPA activity and plasminogen activation in the involuting mammary gland. Our results suggest that GH and prolactin inhibit cell death and ECM remodelling via the IGF-axis and also indicate a novel role for the milk protein alpha s2-casein in this process. We have now established lines of transgenic mice expressing IGFBP-5 on the beta-lactoglobulin promoter to explore its function in greater detail.
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PMID:Insulin-like growth factor binding protein-5 (IGFBP-5) potentially regulates programmed cell death and plasminogen activation in the mammary gland. 1095 8

We have proposed that growth hormone (GH) and prolactin (PRL) interact to suppress apoptosis in the mammary gland. GH increases insulin-like growth factor-I (IGF-I) synthesis whereas PRL suppresses the production of insulin-like growth factor-binding protein-5 (IGFBP-5) in the epithelial cells, which would otherwise inhibit IGF-mediated cell survival. IGFBP-5 was present in milk from involuting glands at high concentrations (approximately 60 microg/ml) and had a high affinity (8.03 x 10(-10) M) for IGF-I, suggesting an inhibitory effect of IGFBP-5 in the mammary gland. IGFBP-5 was present in the micellar fraction of milk and binds specifically to alpha(s2)-casein. Since alpha(s2)-casein also binds plasminogen and tissue-type plasminogen activator (t-PA), resulting in the conversion of plasminogen to plasmin, and since IGFBP-5 binds to plasminogen activator inhibitor-1 (PAI-1), we investigated whether apoptosis and extracellular matrix (ECM) degradation might be coordinately controlled by GH and PRL possibly acting through IGFBP-5. Litters were removed from lactating rats to initiate involution. Plasminogen activation and t-PA activity were both increased dramatically after 48 h and GH and PRL suppressed this response. By contrast, 17beta-oestradiol, progesterone or corticosterone did not influence either process. An antiserum to IGF-I, which blocked systemic IGF-I effects, failed to inhibit the activation of plasminogen or the increase in t-PA, suggesting that paracrine effects of IGF-I may be more important. Teat-sealing, which led to the accumulation of milk without hormonal changes, also led to increases in plasminogen activation and t-PA activity, suggesting that locally produced factors (of which IGFBP-5 is one) are important in controlling ECM remodelling. We propose that GH and PRL inhibit apoptosis and ECM remodelling by a process that involves the control of IGF-I and PAI-1 availability by IGFBP-5, thus allowing these processes to be tightly coordinated.
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PMID:Hormonal control of plasmin and tissue-type plasminogen activator activity in rat milk during involution of the mammary gland. 1105 40

Poly(L-lactic acid) (PLA)-degrading Amycolatopsis sp. strains K104-1 and K104-2 were isolated by screening 300 soil samples for the ability to form clear zones on the PLA-emulsified mineral agar plates. Both of the strains assimilated >90% of emulsified 0.1% (wt/vol) PLA within 8 days under aerobic conditions. A novel PLA depolymerase with a molecular weight of 24,000 was purified to homogeneity from the culture supernatant of strain K104-1. The purified enzyme degraded high-molecular-weight PLA in emulsion and in solid film, ultimately forming lactic acid. The optimum pH for the enzyme activity was 9.5, and the optimum temperature was 55 to 60 degrees C. The PLA depolymerase also degraded casein and fibrin but did not hydrolyze collagen type I, triolein, tributyrin, poly(beta-hydroxybutyrate), or poly(epsilon-caprolactone). The PLA-degrading and caseinolytic activities of the enzyme were inhibited by diisopropyl fluorophosphate and phenylmethylsulfonyl fluoride but were not significantly affected by soybean trypsin inhibitor, N-tosyl-L-lysyl chloromethyl ketone, N-tosyl-L-phenylalanyl chloromethyl ketone, and Streptomyces subtilisin inhibitor. Thus, Amycolatopsis sp. strain K104-1 excretes the unique PLA-degrading and fibrinolytic serine enzyme, utilizing extracellular polylactide as a sole carbon source.
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PMID:Purification and characterization of an extracellular poly(L-lactic acid) depolymerase from a soil isolate, Amycolatopsis sp. strain K104-1. 1113 65

Due to an increase in the activity of phospholipase A(2) (PLA(2)) in various inflammatory diseases, this enzyme may play a key role in the degradation of liposomes and the subsequent release of drug when PEG-liposomes passively target inflammatory tissue. The activity of mammalian secreted phospholipase A(2) (sPLA(2)) in casein stimulated peritoneal fluid was tested toward liposomes of different compositions. Early results indicate only a slight degradation of conventional dipalmitoylphosphatidylcholine (DPPC) liposomes as well as DPPC liposomes incorporated with different concentrations of PEG(2000). However, the DPPC degradation increased to 7% when inclusion of 30 mol% phosphatidylethanolamine (PE) in the lipid bilayer. The increase in degradation may be due to an improvement of the substrate - as it is well known, that PE is a better substrate for the mammalian sPLA(2) than PC. Incorporation of PE into the bilayer may increase the binding properties of the bilayer resulting in improved conditions for the enzymatic attack by sPLA(2). In addition, inhibitory zones of Staphylococcus aureus in an agar diffusion test showed that PLA(2) from Crotalus atrox venom was able to catalyze the release of gentamicin from PEG-liposomes. In conclusion, this study suggest that degradation of the lipid bilayer of PEG-liposomes by PLA(2) result in release of incapsulated drug, e.g. gentamicin and inclusion of PE in the liposomal bilayer, may enhance the activity of the mammalian sPLA(2) toward liposomes composed of DPPC.
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PMID:Activity of mammalian secreted phospholipase A(2) from inflammatory peritoneal fluid towards PEG-liposomes. Early indications. 1128 44

The activity of plasmin (PL), plasminogen (PG), and plasminogen activator (PA) and their correlation with goat milk components and milk clotting parameters were investigated. Seven late-lactating Saanen goats were used to provide milk samples that were analyzed for PL, PG, and PA activity (colorimetric assay) fat, protein, noncasein nitrogen, nonprotein nitrogen, casein content, and somatic cell count (SCC). Milk clotting parameters (rennet coagulating time = coagulation time; K20 = firming rate of curd; A30 = curd firmness) were measured with a formagraph. Average milk yield and composition were similar to those previously observed in other studies. Plasmin, PG, and PA activity, expressed as units/ml, were, respectively, 20.04 +/- 0.94, 3.21 +/- 0.04, and 1154 +/- 57.61. Plasminogen activity was surprisingly low compared with other species (bovine, ovine), but it was consistent with the high activity of PA. A negative significant correlation was observed between PL and milk casein content. The correlation coefficients between PL and casein/protein ratio and PA and casein/protein ratio were negative and significant. A positive significant correlation was observed between PL and rennet clotting time and PA and rennet clotting time. Also positive was the correlation between PL and K20 and PA and K20. The plasmin activity was negatively correlated with A30. High plasmin and plasminogen activator activity in goat milk appeared to be negatively related with coagulating properties in late lactation, most probably via degradation of casein due to plasmin activity.
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PMID:Plasminogen activation system in goat milk and its relation with composition and coagulation properties. 1151 1


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