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)

In a primary human endometrial cell culture, the addition of progesterone resulted in an approximately 2-fold increase in the amount of tissue-type plasminogen activator (t-PA) released into the culture media, with the minimal effective dose being 10(-7) M. In contrast, progesterone significantly reduced the release of urokinase-type PA (u-PA). Endometrial cells are known to release a major PA inhibitor, PAI-1. Progesterone stimulated the release of PAI-1. These observed effects of progesterone seem to be mediated through the progestin receptor in that R5020, a specific ligand for progestin receptor, mimicked the effects of progesterone, and RU486, an antagonist of progesterone, completely eliminated the effects of progesterone. It is notable that estradiol, when added alone or in combination with progesterone, caused no discernible effect on the release of PAs and PAI-1. These results suggest that progesterone is a key hormone in regulating the PA/plasmin system in the human endometrium, thereby playing a pivotal role in implantation and ensuing embryonal development.
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PMID:Effects of steroid hormones on fibrinolytic system in cultured human endometrial cells. 759 99

Progesterone acts on the estradiol (E2)-conditioned human endometrium to induce decidualization of stromal cells. Consistent with these differential hormone actions in vivo, progestins regulate several end points of decidualization in human endometrial stromal cell monolayers, and E2 augments the effects of progestin. This study shows that in vitro decidualization of the stromal cells is accompanied by diminished plasminogen activator (PA) expression. Polyacrylamide gel electrophoretic separation after immunoprecipitation of biosynthetically labeled PAs revealed that medroxyprogesterone acetate (MPA) lowered levels of secreted tissue type PA (tPA) at 67 kilodaltons and urokinase type PA (uPA) at 55 kilodaltons. These levels were reduced further by E2 plus MPA despite a lack of response to E2 alone. Although tPA activity was readily measured by a chromogenic assay, detection of uPA activity required prior activation, indicating that uPA is released as the pro-uPA zymogen. Comparisons of levels of immunogenic PAs, as measured by specific enzyme-linked immunosorbent assays, with the corresponding catalytic activities revealed selective progestational inhibition of PA activity vs. antigen after 3 days of experimental incubation. Thus, 10(-7) mol/L MPA produced about a 2-fold greater reduction of levels of PA activity than that of its corresponding antigen. More strikingly, 10(-8) mol/L E2 plus 10(-7) mol/L MPA virtually eliminated both tPA activity (99% inhibition; P < 0.005) and uPA activity (93% inhibition; P < 0.005); the reductions in levels of the corresponding antigens were only about 50% of the control levels and did not attain statistical significance. Only after 3-6 days of incubation with E2 plus MPA was statistically significant inhibition achieved for immunogenic levels of both tPA (P < 0.05) and uPA (P < 0.005). Preferential inhibition of levels of PA activities compared with those of the corresponding PA antigens reflects the action of the potent PA inhibitor PAI-1. Thus, the concentration of PAI-1 in the stromal cell-conditioned medium at the end of 0-3 days exceeded those of tPA and uPA, respectively, by 28- and 12-fold in response to MPA and by 52- and 25-fold in response to E2 plus MPA. Extrapolation of these in vitro results to the events of the luteal phase, whose steroidal milieu is mimicked by E2 plus MPA, indicates that decidual cell-derived PAI-1 is a key regulator of proteolytic degradation of extracellular matrix and fibrinolysis during implantation and menstruation.
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PMID:Plasminogen activator activity during decidualization of human endometrial stromal cells is regulated by plasminogen activator inhibitor 1. 762 51

Progesterone stimulates differentiation and inhibits the growth of endometrial tissue. Also, progesterone reduces plasminogen activator (PA) activity, which implies reduced turnover of extracellular matrix proteins in the secretory phase. To elucidate the mechanism responsible for reduced PA activity, primary cultures of human endometrial stromal cells were stimulated with estradiol and progesterone. Conditioned media were assayed for urokinase-type and tissue-type PA (u-PA and t-PA, respectively), PA inhibitor-1 (PAI-1), and PA activity. Binding of [125I]u-PA and [125I]u-PA:PAI-1 complex to the u-PA receptor and clearance of these ligands were studied. The PA activity of conditioned medium decreased after stimulation with progesterone, and this was secondary to a decrease in u-PA, but not t-PA, and an increase in PAI-1. Northern blot analysis showed induction of PAI-1 messenger ribonucleic acid, whereas the content of u-PA messenger ribonucleic acid was not influenced. Furthermore, the number of free u-PA receptor-binding sites was increased by estradiol and progesterone. The stromal cells degraded complexed u-PA more efficiently than free u-PA, and degradation of both ligands was inhibited by colchicine, chloroquine, and methylamine. Degradation was increased after hormone treatment, and this was apparently due to increased ligand binding, because neither ligand affinity nor the relative rate of degradation was increased. Increased expression of u-PA receptor-binding sites was not regulated on the transcriptional level, but may result from posttranslational mechanisms, such as decreased turnover of the receptor. Activation of plasminogen by receptor bound u-PA initiates a cascade of proteolytic events in the extracellular matrix that is important during tissue proliferation. Our data suggest that differentiated endometrial stroma in the secretory phase regulates extracellular proteolysis by increased elimination of u-PA through increased release of PAI-1 and increased u-PA receptor density.
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PMID:Progesterone stimulates degradation of urokinase plasminogen activator (u-PA) in endometrial stromal cells by increasing its inhibitor and surface expression of the u-PA receptor. 767 23

Changes of plasminogen activators (PA) during different stages of development of the corpus luteum, and their possible physiological role in luteolysis were studied in rhesus monkeys. It was demonstrated for the first time that monkey corpus luteal cells not only produce PA, but that the function of the corpus luteum is also closely related to the activity of this enzyme system. Generally, the life span for a corpus luteum in monkey is approximately 14-16 days, its demise beginning thereafter. In the present study, we found that urokinase in the corpus luteum is higher on day 5 and day 10 after human chorionic gonadotrophin injection, while the tissue type (t) PA is mainly produced on day 13 when luteolysis may take place. Progesterone production remained high on day 5 and day 10 and decreased dramatically from day 13, indicating the important role of tPA but not urokinase (u) PA in suppressing luteal function. When purified tPA (but not uPA) monoclonal antibody was added to luteal cell culture to neutralize endogenously produced tPA activity, progesterone production in the cells was increased significantly. Interestingly, prolactin alone was capable of increasing PA production by luteal cells; prolactin together with luteinizing hormone, however, had a synergistic luteotrophic effect.
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PMID:The possible involvement of tissue type plasminogen activator in luteolysis of rhesus monkey. 830 Aug 20

During progesterone-induced decidualization of estradiol (E2)-primed human endometrial stromal cells (HESCs), the interstitial-type extracellular matrix (ECM) of the follicular phase endometrium is transformed in the luteal phase to a mixture of residual interstitial- and new basal laminar-type components. This transformation is accelerated by reduced proteolytic activity of HESCs undergoing decidualization (DZ). In cultured HESCs, progestins, but not E2, induce the expression of several DZ markers, and E2 enhances these effects despite the lack of response to E2 alone. Using this well-characterized in vitro DZ model we evaluated the expression of plasminogen activators (PAs), which degrade ECM components that undergo rapid turnover, and matrix metalloproteinases (MMPs), which degrade the bulk of ECM components. Medroxyprogesterone acetate (MPA) inhibited the catalytic activity of urokinase-type PA (uPA) and tissue-type PA (tPA) as well as the expression of such MMPs as interstitial collagenase (MMP-1) and stromelysin-1 (MMP-3). Moreover, E2 + MPA elicited greater inhibitory effects on the expression of all of these proteases. Progestin inhibition of PA activities reflected reciprocal upregulation in the output of the PA inhibitor PAI-1, which produced large molar excesses of PAI-1 compared with the PAs in HESC-conditioned medium. By contrast, the tissue inhibitor of the MMPs, TIMP1, as well as gelatinase A (MMP-2), was constitutively expressed by the HESCs. In the absence of implantation, menstruation-associated degradation of the functional endometrial ECM is triggered by withdrawal of circulating ovarian steroids. This process was evaluated in cultured HESCs that were first decidualized during 10 days of exposure to E2 + MPA, and then withdrawn to steroid-free medium with and without the antiprogestin RU 486. As expected, steroid withdrawal reversed progestin-inhibited PA activity as well as the expression of MMP-1 and MMP-3 and progestin-enhanced PAI-1; much greater reversal was observed in medium supplemented with RU 486. Unlike the changes in PAI-1, neither TIMP1, nor MMP-2 expression was affected by withdrawal to steroid-free or to RU 486-medium. By altering the composition of the ECM of the luteal phase endometrium, progestin-elicited inhibition of the PAs, uPA and tPA, as well as that of the MMPs, MMP-1 and MMP-3, modulates trophoblast adhesion, migration and differentiation. Conversely, steroid withdrawal elicited increases in uPA, MMP-1 and MMP-3 activities would promote endometrial sloughing by degrading the mixture of decidual cell-derived basement membrane-like proteins and interstitial components that comprise the stromal ECM of the perimenstrual endometrium.
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PMID:Implications of decidualization-associated protease expression in implantation and menstruation. 1040 70

Current research suggests that the appearance of endometrial integrins and pinopode appearance signal the opening of the receptive phase of the endometrium. These integrins may be activated by the interleukin-1 system (IL-1). IL-1beta, expressed by the blastocyst, induces vascular endothelial growth factor (VEGF) which, in turn, promotes angiogenesis and integrin expression in endometrial cells. The IL-1 system also triggers the expression of gamma interferon (IFN-gamma) from T lymphocytes. Decidual natural killer (NK) lymphocytes interact with invading trophoblast to generate leukaemia inhibitory factor (LIF). LIF induces uPA and gelatinase, enzymes which play a crucial role in trophoblastic invasion. Progesterone is a potent inhibitor of LIF, while oestrogen is a potent inducer. Oestrogen in serum reflects follicular IL-1beta level and correlates with the outcome of embryo transfer after in vitro fertilization (IVF). Progesterone induces nitric oxide (NO) synthesis in the decidua, and NO promotes local vasodilatation and uterine quiescenceMeasurement of placental protein 14 (PP14, glycodelin-A) in serum may be of value as a screening test for implantation potential. However, human chorionic gonadotrophin (hCG) remains the most reliable predictor of successful implantation and pregnancy viability. An ovulation + 14 hCG level < 50 IU/l is often predictive of a non-viable outcome, while an ovulation + 21 hCG of < 200 IU/l always indicates a non-viable pregnancy. hCG secretion by invading trophoblast appears to be negatively modulated by endothelin-1 (ET-1) and prostaglandin F(2alpha)(PGF2alpha), while tissue growth factors and collagenases are positive modulators of hCG expression.ProalphaC, an inhibin pro-monomer, may have some value in monitoring corpus luteum function. Inhibin A, activin A and follistatin all rises throughout pregnancy and peak at 36 weeks of gestation. Relaxin is another ovarian hormone that may have a role in predicting implantation. Relaxin induces placental protein 14 (PP14, glycodelin-A) expression in a receptive endometrium, and measurement of serum PP14 may be of value as a screening test for implantation potential.
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PMID:Endocrinology of the peri-implantation period. 1102

Progesterone pretreatment of ovariectomized rat uteri increases the number of synchronously proliferating stromal cells in response to estradiol 17-beta. To identify the signals involved in stimulating synchronous proliferation, sexually mature ovariectomized rats were injected with progesterone (2 mg) for 3 consecutive days. Estradiol 17-beta (0.2 microg) was administered to initiate cell cycle entry. Uterine samples were removed at various times after hormone administration and changes in wingless (Wnt) pathway effectors and gene targets were identified by microarray. Progesterone pretreatment decreased glycogen synthase kinase-3beta (GSK-3beta) and increased expression of T-cell factor/lymphoid enhancer factor (TCF/LEF). GSK-3beta protein decreased markedly in the uterine stroma of progesterone-pretreated uteri with the concomitant appearance of beta-catenin in these stromal cells. Translocation of beta-catenin from the cytosol to the nuclei in progesterone-pretreated stromal cells was stimulated in response to estradiol. Beta-catenin binding to TCF/LEF increased (P<0.05) in progesterone-pretreated uteri in response to estradiol. Progesterone stimulated the expression of the Wnt target gene urokinase plasminogen activator receptor (uPA-R) in the periluminal uterine stromal cells. The expression of uPA-R increased in progesterone-pretreated stromal cells in response to estradiol administration. Together, the results indicate that progesterone initiates Wnt signaling in the uterine stroma by down-regulating GSK-3beta. However, nuclear translocation of beta-catenin and sufficient complex formation with TCF/LEF to activate stromal cell cycle entry requires estradiol. Stimulation of a uterine stromal cell line to proliferate and differentiate resulted in beta-catenin accumulation, suggesting that endocrine-dependent Wnt signaling controls proliferation and differentiation (decidualization).
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PMID:Progesterone initiates Wnt-beta-catenin signaling but estradiol is required for nuclear activation and synchronous proliferation of rat uterine stromal cells. 1717 Feb 12

The aim of this study was to determine the effect of norgestomet treatment, in the absence or the presence of a functional corpus luteum (CL), on plasminogen activators activity (PAA) in the cervical mucus and the endometrium in dairy cows. Eleven days after oestrus (Day 0 = oestrus), 38 cows were randomly assigned to one untreated control group (n = 9) and three treatment groups (S(1), S(2) and S(3)). Animals of S(1) group (n = 9) received an implantation of norgestomet on the outer surface of the ear for 8 days, simultaneous injection of oestradiol valerate 5 mg and norgestomet 3 mg, i.m., and on Day 19 an injection of ECG 500 IU, i.m. Animals of S(2) group (n = 11) received the treatment of S(1) group, plus an administration of PGF(2)alpha on Day 10 for the regression of CL. Animals of S(3) group received the treatment of S(2) group, plus two additional norgestomet implants inserted on Day 16 for 36 h. Both types of plasminogen activators [the tissue-type (t-PA) and the urokinase-type (u-PA)] were detected in the cervical mucus and the endometrium of the cows. Plasminogen activators activity in the cervical mucus was higher in control group than in S(1), S(2) and S(3) groups (P < 0.001). In contrast, endometrial PAA did not differ among groups (P > 0.05). Oestradiol-17beta concentrations on Day 21 were higher in S(2) group than in control group (P < 0.01) and S(3) group (P < 0.05). Progesterone concentrations did not differ among groups (P > 0.05). Oestradiol-17beta concentrations could positively affect cervical mucus PAA in control group (P < 0.1), but not in other groups (P > 0.05). These findings suggest that control of estrous cycle by norgestomet administration, in dairy cows, exerts a suppressive effect on plasminogen activators synthesis and/or secretion in the cervical mucus, regardless of the absence or the presence of the CL. On the contrary, endometrial PAA is not affected by norgestomet treatment.
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PMID:Effect of norgestomet treatment on plasminogen activator activity in the cervical mucus and the endometrium in dairy cows. 1787 77

Biomarkers of breast cancer are necessary for prognosis and prediction to chemotherapy. Prognostic biomarkers provide information regarding outcome irrespective of therapy, while predictive biomarkers provide information regarding response to therapy. Candidate prognostic biomarkers for breast cancers are growth factor receptors, steroid receptors, Ki-67, cyclins, urokinase plasminogen activator, p53, p21, pro- and anti-apoptotic factors, BRCA1 and BRCA2. But currently, the predictive markers are Estrogen and Progesterone receptors responding to endocrine therapy, and HER-2 responding to herceptin. But there are numerous breast cancer cases, where tamoxifen is ineffective even after estrogen receptor positivity. This lead to search of new prognostic and predictive markers and the number of potential markers is constantly increasing due to proteomics and genomics studies. However, most biomarkers individually have poor sensitivity or specificity, or other clinical value. It can be resolved by studying various biomarkers simultaneously, which will help in better prognosis and increasing sensitivity for chemotherapeutic agents. This review is focusing on growth factor receptors, apoptosis markers, signaling cascades, and their correlation with other associated biomarkers in breast cancers. As our knowledge regarding molecular biomarkers for breast cancer increases, prognostic indices will be developed that combine the predictive power of individual molecular biomarkers with specific clinical and pathologic factors. Rigorous comparison of these existing as well as emerging markers with current treatment selection is likely to see an escalation in an era of personalized medicines to ensure the breast cancer patients receive optimal treatment. This will also solve the treatment modalities and complications related to chemotherapeutic regimens.
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PMID:Growth factor receptors and apoptosis regulators: signaling pathways, prognosis, chemosensitivity and treatment outcomes of breast cancer. 2155 49