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)

When human granulocytes were stimulated with the chemotactic peptide FNLPNTL (N-formyl-norleucyl-leucyl-phenylalanyl-norleucyl-tyrosinyl- lysin; in the presence of cytochalasin B), proteolytic enzymes were released which prevented activation of tumor-cell derived pro-uPA by plasmin. Elastase was identified by use of eglin C (elastase inhibitor) and an inhibitory monoclonal antibody to elastase as the functional proteolytic enzyme in these granulocyte supernatants. Purified human granulocyte elastase cleaves pro-uPA at amino acid position lle159-lle160 thus generating an enzymatically inactive two-chain form of uPA, as judged by N-terminal amino acid sequence analysis. An additional minor elastase-mediated cleavage site was detected at position Thr165-Thr166. This form of uPA was indistinguishable by SDS-PAGE from plasmin-generated enzymatically active HMW-uPA. Action of plasmin on the proenzyme form of uPA (pro-uPA) generates an enzymatically active uPA-molecule (high molecular weight form; HMW-uPA) which is cleaved at amino acid position Lys158-lle159 (Mr = 33,000 (B-chain) and 22,000 (A-chain). Thus elastase cannot substitute for plasmin in the proteolytic activation of pro-uPA to enzymatically active HMW-uPA. Enzymatically active HMW-uPA, however, was not affected by elastase. Elastase-containing granulocytes were identified by immunohistochemical staining of elastase in breast cancer tissue. Granulocytes were located close to the tumor cells and also in the tumor stroma surrounding the tumor nests. These tumor cells contain pro-uPA. Evidently, the conversion of tumor cell pro-uPA into enzymatically active HMW-uPA is controlled by elastase released from granulocytes into the tumor tissue.
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PMID:Human tumor cell urokinase-type plasminogen activator (uPA): degradation of the proenzyme form (pro-uPA) by granulocyte elastase prevents subsequent activation by plasmin. 183 19

Supernatant obtained from granulocytes stimulated in the presence of cytochalasin B by the chemotactic peptide N-formyl-norleucyl-leucyl-phenylalanyl-norleucyl-tyrosyl- lysine displayed an inhibitory effect on the plasmin-dependent conversion of tumor urokinase-type plasminogen activator proenzyme (pro-uPA) to the active form of uPA. Moreover, the supernatant was also found to inhibit the fibrinolytic activity of human vulva (A431) and breast (MCF7) carcinoma cell lines, which contain large amounts of pro-uPA, by 87% and 96%, respectively. By using eglin C (elastase inhibitor) and a monoclonal antibody to elastase (proteolytic activity blocker of the enzyme), elastase was identified as the key enzyme of the supernatant in these phenomena. Purified elastase converted pro-uPA to an enzymatically inactive molecule composed of two polypeptide chains of Mr = 33,000 and 22,000 linked to each other by a disulfide bond. Elastase-containing granulocytes were identified by immunohistochemistry techniques in the tissues of squamous cell carcinoma and adenocarcinoma of uterus. The cells were found close to the tumor cells and in the stroma surrounding the tumor nests. By immunohistochemical staining, uPA was also found in the tumor cells. Evidently, elastase released by chemotactically activated granulocytes, which are attracted into tumor tissues, may inhibit the conversion of pro-uPA to enzymatically active uPA in the tumor cells.
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PMID:Inactivation of human tumor cell pro-urokinase by granulocyte elastase. 212 85

Proteolytic enzymes released from granulocytes upon stimulation with the chemotactic N-formyl peptide FNLPNTL (in the presence of cytochalasin B) prevented activation of tumor cell single-chain urokinase-type plasminogen activator (pro-uPA) by plasmin. Elastase was identified by the use of eglin C (elastase inhibitor) and a monoclonal antibody to elastase as the functional proteolytic enzyme in granulocyte supernatants. Action of purified granulocyte elastase on pro-uPA generated enzymatically inactive two-chain uPA linked by disulfide bridges which was indistinguishable by SDS-PAGE from plasmin-generated HMW-uPA. The major elastase cleavage site in pro-uPA was located between Ile159 and Ile160. a minor one between Thr165 and Thr166. Elastase cannot substitute for plasmin in the proteolytic activation of pro-uPA to enzymatically active HMW-uPA. However, when pro-uPA was first activated by plasmin to form enzymatically active HMW-uPA, this enzymatic activity was not impaired by subsequent elastase treatment.
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PMID:Elastase released from human granulocytes stimulated with N-formyl-chemotactic peptide prevents activation of tumor cell prourokinase (pro-uPA). 252 37

The rapidly acting plasminogen activator inhibitor (PAI) purified from cultured bovine aortic endothelial cells (BAEs) was inactivated during iodination with chloramine T and other oxidizing iodination systems. Inactivation was observed in the absence of iodine, suggesting that the loss of activity resulted from the oxidizing conditions employed. In an attempt to further study the nature of this inactivation, the PAI was treated with chloramine T under conditions that specifically oxidize methionine and cysteine residues. Both PAI inhibitory activity and the ability of the PAI to form complexes with tissue-type PA were decreased in a dose-dependent manner by such treatment. The PAI was more sensitive to oxidative inactivation than urokinase, elastase, and alpha 1-protease inhibitor. Incubation of the chloramine T inactivated PAI with methionine sulfoxide peptide reductase in the presence of dithiothreitol (DTT) restored more than 90% of the PAI activity. The reductase is a DTT-dependent enzyme that specifically converts methionine sulfoxide to methionine. Little activity was restored by either the reductase or DTT alone. These results indicate that the oxidation of at least one critical methionine residue is responsible for the loss of PAI activity upon iodination. In this respect, the BAE PAI resembles alpha 1-protease inhibitor, a well-characterized elastase inhibitor that also is inactivated by oxidants. Both inhibitors are members of the serine protease inhibitor superfamily (Serpins), and both have a methionine residue in their reactive center.
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PMID:Inactivation of plasminogen activator inhibitor by oxidants. 309 87