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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The biological effects of estriol (E3) have been studied in three estrogen targets, namely, the rat uterus in vivo and in vitro, in primary human endometrial cell cultures and in MCF-7 human breast cancer cells in culture. Studies on the temporal relationships between estrogen receptor binding and biological responses in the uterus using estriol and several more long-acting estriol derivatives, namely, 17 alpha-ethynyl estriol, estriol-3-cyclopentyl ether, and 17 alpha-ethynyl estriol-3-cyclopentyl ether, indicate that estriol is a short-acting compound with a brief duration of action. Estriol is a poor stimulator of uterine growth and plasminogen activator activity in vivo. Chemical modifications of the estriol molecule produce long-acting derivatives that result in a prolonged input of hormone receptor complexes into the nucleus and a prolonged and marked stimulation of uterine growth. In human endometrial cells in primary tissue culture, E3 has 12% the affinity of estradiol (E2) for cytosol estrogen receptor and it is quite effective yet slightly less potent than estradiol in stimulation of progesterone receptor synthesis. Low concentrations of E3 (10(-10) M) stimulate growth of MCF-7 cells in vitro and dose-response curves show E3 to be only slightly less effective than E2. In these endometrial and breast cancer cell systems in vitro, there is no metabolism of E3 while E2 is metabolized to estrone. Hence, estriol is an effective estrogen in vitro. In vivo, it is short-acting, but it can be made a full estrogen agonist when given at a sufficiently high concentration or in a chemically modified form which prolongs its activity by enabling effective concentrations of the compound to be maintained in the blood and in target tissues.
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PMID:Biology and receptor interactions of estriol and estriol derivatives in vitro and in vivo. 672 48

Human plasminogen activators were compared immunologically in both a double-diffusion technique and quenching experiments on the fibrinolytic activities of the activators. Antisera against HMW and LMW urokinase and an antiserum against highly purified tissue plasminogen activator from human uterus were used. It was found that uterine tissue plasminogen activator and urokinase are two immunologically distinct plasminogen activators. The occurrence of the two kinds of plasminogen activators in human tissues and body fluids was studied on the basis of the quenching of the activities by antibodies. In tissue extracts, mainly tissue plasminogen activator was found. Seminal plasma exhibited a high plasminogen activator activity, consisting of both urokinase and tissue plasminogen activator-related activators. Urine contained a small amount of tissue plasminogen activator-related activator in addition to urokinase. The low plasminogen activator activities of saliva and tears were completely attributed to activators related to tissue plasminogen activator.
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PMID:Immunological characterization of plasminogen activator activities in human tissues and body fluids. 678 83

The plasminogen activator secreted by a cultured human melanoma cell line was purified and compared with urokinase and with tissue plasminogen activator from human uterus. The purification procedure consisted of chromatography on zinc chelate-agarose, concanavalin A-agarose, and Sephadex G-150 in the presence of 0.01% (v/v) Tween 80. The purified material was obtained from the culture medium with a yield of 46% and a purification factor of 263. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed one main band with a molecular weight of about 72,000, and in the presence of reducing agents, two bands of 33,000 and 39,000. Addition of the protease inhibitor Aprotinin to the culture media and column buffers yielded a one-chain plasminogen activator with a molecular weight of about 72,000. One molecule of activator reacted with about one molecular of [3H]diisopropylfluorophosphate. The melanoma plasminogen activator and the uterine tissue plasminogen activator appeared to be very similar on dodecyl sulfate-polyacrylamide gel electrophoresis, amino acid analysis, and amidolytic properties. Both activators bound to fibrin clots, while urokinase did not. In immunodiffusion, as well as in quenching experiments of the fibrinolytic activities, the melanoma plasminogen activator appeared to be immunologically identical with the uterine tissue plasminogen activator, but unrelated to urokinase. All these findings indicate that the plasminogen activator secreted by human melanoma cells in culture is very similar to, or identical with, the plasminogen activator found in normal tissue, but different from urokinase.
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PMID:Purification and characterization of the plasminogen activator secreted by human melanoma cells in culture. 678 58

We have used a sensitive and quantitative assay to investigate the hormonal regulation of plasminogen activator (PA) activity in the rat uterus. PA activity is increased 5-fold (per U protein or DNA) by low physiological (0.1 micrograms) doses of estradiol, with increases in activity first observed at approximately 12 h. The stimulation of PA activity shows strict specificity among the steroid hormones, being stimulated by estrogens only or by high doses of dihydrotestosterone, which are known to affect the estrogen receptor system, and this stimulation is suppressed markedly by triphenylethylene antiestrogens. Comparative dose-response studies with a variety of estrogens of different uterotropic potencies indicate a good correlation between the potencies of different estrogens in stimulating PA activity and uterine growth (diethylstilbestrol = 17 beta-estradiol greater than estrone = 17 alpha-estradiol greater than estriol), with the exception of the zearalanol estrogen P-1496, which was consistently a potent stimulator of PA activity while being a very weak uterotropic agent. These studies suggest that increases in uterine PA levels may serve as a good marker of estrogen action in the uterus. Although the role of PA in uterine function remains unknown at present, its relatively large increase (up to 25-fold increase in content per uterus) may play a role in tissue remodeling during uterine growth.
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PMID:Uterine plasminogen activator activity: modulation by steroid hormones. 720 82

Embryo implantation in the mouse is an invasive process and requires the action of proteinases, including plasminogen activator (PA) and metalloproteinases. After the implanting embryo establishes close contact with the endometrium, the invasion process begins, at least in part, through interactions of the embryo with the extracellular matrix in the endometrium. This study determined whether embryo interaction with extracellular matrix components would affect the secretion of PA in vitro. PA in vitro. Mouse embryos were collected from the uterus on Day 3.5 of development, just before implantation, and were cultured dishes precoated with bovine serum, plasma fibronectin, or BSA (control). Embryos cultured on serum- or fibronectin-coated dishes secretes significantly more PA than those cultured on BSA. The effect of fibronectin was inhibited by hexapeptides that contained the integrin-recognizing Arg-Gly-Asp sequence. This indicates that the action of fibronectin in enhancing PA secretion is mediated through its receptor (integrins) in the embryo. Fibronectin fragments reproduced the effect of the whole fibronectin molecule, suggesting that the clustering of integrins by specific ligands is responsible, at least in part, for the increase PA secretion. The increase in PA secretion was a specific response to fibronectin rather than a reflection of increased total protein secretion, and was at least partially a result of the increased steady-state level of PA mRNA in the cultured embryos. Laminin was as effective as fibronectin in promoting PA secretion. Epidermal growth factor increased PA secretion, probably by promoting the interaction of the embryos with the extracellular matrix. In summary, our findings indicate that the interactions of the implanting embryos with their extracellular matrix may regulate trophoblast invasion by controlling PA secretion.
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PMID:Regulation of urokinase plasminogen activator production in implanting mouse embryo: effect of embryo interaction with extracellular matrix. 872 26

Collagens of most connective tissues are subject to continuous remodelling and turnover, a phenomenon which occurs under both physiological and pathological conditions. Degradation of these proteins involves participation of a variety of proteolytic enzymes including members of the following proteinase classes: matrix metalloproteinases (e.g. collagenase, gelatinase and stromelysin), cysteine proteinases (e.g. cathepsin B and L) and serine proteinases (e.g. plasmin and plasminogen activator). Convincing evidence is available indicating a pivotal role for matrix metalloproteinases, in particular collagenase, in the degradation of collagen under conditions of rapid remodelling, e.g. inflammation and involution of the uterus. Under steady state conditions, such as during turnover of soft connective tissues, involvement of collagenase has yet to be demonstrated. Under these circumstances collagen degradation is likely to take place particularly within the lysosomal apparatus after phagocytosis of the fibrils. We propose that this process involves the following steps: (i) recognition of the fibril by membrane-bound receptors (integrins?), (ii) segregation of the fibril, (iii) partial digestion of the fibril and/or its surrounding non-collagenous proteins by matrix metalloproteinases (possibly gelatinase), and finally (iv) lysosomal digestion by cysteine proteinases, such as cathepsin B and/or L. Modulation of this pathway is carried out under the influence of growth factors and cytokines, including transforming growth factor beta and interleukin 1 alpha.
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PMID:Phagocytosis and intracellular digestion of collagen, its role in turnover and remodelling. 876 55

We have described recently a panel of metastasis-associated antigens expressed on a rat pancreatic tumor. One of these molecules, recognized by the monoclonal antibody C4.4 and named accordingly C4.4A, was under physiological conditions expressed only in the gravid uterus and on epithelial of the upper gastrointestinal tract. The cDNA of the antigen has been isolated and cloned. The 1,637 b cDNA codes for a 352 amino acid long glycosylphosphatidyl-inositol (GP) anchored molecule, whose molecular weight varies in different cells between 94-98 kD according to the degree of N- and O-glycosylation. Data base searches have revealed a low degree of homology to the receptor for the plasminogen activator (uPAR). After intrafootpad and intravenous application of C4.4A transfected and mock-transfected tumor cells, an increased number of lung nodules was detected with the former, whereby the individual metastatic nodules amalgamated without any encapsulation of the tumor tissue. Furthermore, C4.4A is involved in adhesion to laminin and, although transfection of a non-metastasizing tumor line with the molecule was not sufficient, constitutively C4.4A-positive tumor cells penetrated through matrigel. This process could be completely prevented by C4.4. Finally, we could demonstrate that uPA, albeit weakly, bound to the C4.4A molecule. In view of the observed influence of C4.4A on metastasis formation and matrix penetration it is tempting to speculate that this newly described metastasis-associated molecule may exert functional activity similar to the uPAR, i.e. via activation of matrix degrading enzymes. By the very restricted expression of the molecule in the adult organism, modulation of C4.4A could well be of therapeutic interest.
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PMID:Cloning and functional characterization of a new phosphatidyl-inositol anchored molecule of a metastasizing rat pancreatic tumor. 978 43

Changes in plasminogen activator are associated with the reproductive tissue remodelling that occurs during growth. Given the trophic effects of relaxin on the pig uterus and cervix, the present study was designed to examine the impact of relaxin on urokinase and tissue-type plasminogen activator (uPA and tPA) protein and activity in the uterus and cervix of prepubertal pigs. After relaxin administration in vivo to induce growth of the immature uterus and cervix, plasminogen activator activity was measured in uterine flushes and uterine and cervical tissue using a chromogenic substrate assay. Immunoreactive uPA and tPA protein in uterine flushes and uterine and cervical tissue was detected by western blotting. Urokinase plasminogen activator activity was significantly higher (P < 0.05) in uterine flushes from relaxin-treated animals than in controls. However, there was no change in uterine flush tPA activity or protein in response to in vivo relaxin treatment. There was no evidence for acid-labile inhibitors of plasminogen activator in uterine flushes of any of the animals. Cell-associated uterine tissue uPA and tPA activity, as well as protein, were similar in relaxin-treated and control prepubertal pigs. In the cervix, cell-associated tPA activity decreased significantly (P < 0.05) in relaxin-treated animals, while cervical uPA activity was unchanged. These results support the view that at least one means by which relaxin promotes pig uterine growth is by increasing uterine secretion of uPA. In addition, these studies suggest that relaxin administration in vivo to prepubertal gilts has tissue-specific effects with respect to plasminogen activator.
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PMID:Regulation of urokinase- and tissue-type plasminogen activator by relaxin in the uterus and cervix of the prepubertal gilt. 987 63

At present the physiological role of most oviductal proteins remains unknown. In this work, we present evidence that the oviductal secretion as well as the crude oviductal tissue-extract show proteolytic-like esterase and amidase activity. The proteolytic activity of the oviductal enzymes was higher in the oviducts of superovulated hamster females than in those of normal ones, indicating that gonadotrophic hormones would stimulate the synthesis and secretion of these enzymes. Some of their properties were analyzed in the 15,600-g supernatant of both oviductal tissue extracts (OE) and oviductal fluid (OF). The enzymatic activity toward the synthetic substrates p-tosyl-l-arginine methyl ester-HCl (TAME) and alpha-N-benzoyl-dl-arginine-p-nitroanilide HCl (BAPNA) was activated by calcium ions, reached a maximum at pH 7.5, and was inhibited by soybean trypsin inhibitor (SBTI), N-alpha-p-tosyl-l-lysine chloromethyl ketone HCl (TLCK), phenyl methyl sulfonyl fluoride (PMSF), and benzamidine. The OE glycoprotein fraction recognized by WGA-Sepharose affinity columns (37% total proteins) showed proteolytic activity with properties similar to the OE and OF enzymes. The protease activity could be ascribed to a plasminogen activator (PA) detected in the Triton X-100 treated tissue crude membrane fraction (Triton-CMF) and in the oviductal secretion of the superovulated females. In the Triton-CMF fraction, 100% of the proteolytic activity was plasminogen-dependent. The use of amiloride, a selective urokinase-type plasminogen activator (uPA) inhibitor, shows that 90% of this activity was due to a tissue-type plasminogen activator (tPA) and 10% to uPA whereas in the uterus 100% of the activity was tPA. Only a small percentage of the OF proteolytic activity was plasminogen-dependent, probably due to the presence of PA inhibitors in this medium.
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PMID:Proteases with plasminogen activator activity in hamster oviduct. 1060 73

We have investigated plasmin mediated proteolysis associated with trophoblast invasion during early stages of pregnancy in the rhesus monkey. In situ hybridization and immunocytochemical localization were used to define the cellular and tissue distribution of urokinase plasminogen activator (uPA), plasminogen activator inhibitor type 1 (PAI-1) and 2 (PAI-2) and urokinase receptor in early monkey placenta and uterus. Our results indicate: (1) uPA is expressed in proliferating and invasive cytotrophoblast located in chorionic villi as well as in extravillous trophoblast associated with uterine arterioles. This raises the possibility that urokinase may play an important role in trophoblast invasion. (2) PAI-1 mRNA is specifically localized in two areas where invasive trophoblast cells encounter maternal tissue directly. The extravillous cytotrophoblast cells at the maternofetal junction express PAI-1 mRNA. The invasive endovascular trophoblast cells within the uterine arterioles also express PAI-1 mRNA. The location sensitive expression of PAI-1 mRNA at the maternofetal junction may imply a protective function of this protease inhibitor that might be induced through interaction with decidual cells. (3) Urokinase receptor antigen has also been found at the maternofetal junction and in endovascular trophoblast cells of the invaded maternal blood vessel. (4) PAI-2 immunoreactivity is found in association with cytotrophoblast cells in anchoring choronic villi suggesting its association with early placentation. In conclusion, we propose that the plasmin/plasminogen activator system may not only regulate extracellular matrix degradation, but also modify migration and invasive behaviour of extravillous trophoblast cells, during early placentation.
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PMID:Expression of urokinase, plasminogen activator inhibitors and urokinase receptor in pregnant rhesus monkey uterus during early placentation. 1073 41


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