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)

The literature on tumor distinctive markers in ovarian cancer has been reviewed. Various immunological and biochemical approaches have been attempted for the diagnosis and management of patients with ovarian cancer. The complex spectrum of antigens that can be detected in human ovarian cancer consists of several tumor-associated antigens, fetal or carcinoembryonic antigens, carcinoplacental markers, and normal tissue antigens. We have described and partially characterized two ovarian tumor-associated antigens designated as OCAA and OCAA-1, which seem to have potential for the immunodiagnosis of ovarian cancer. Several other investigators have carried out similar studies, but in general their serological characterization of these antigens has been limited. The well-defined embryonic proteins that have been examined in the ovarian cancer include carcinoembryonic antigen (CEA), alpha-fetoprotein (alpha-fp), beta-oncofetal antigen (BOFA), Regan and Nagao isoenzymes and human chorionic gonadotropin (HCG). The presence of pregnancy-zone protein (PZP) has also been reported in ovarian cancer. In addition, several normal tissue components include fibrin-fibrinogen degradation products (FDP), alpha 1-globulin, and urokinase have been found associated with ovarian cancer. Both humoral antibodies and cell-mediated immune responses against tumor-associated antigens can be measured in ovarian cancer patients. In addition, serum factors, which block cellular immune reactions, have been identified. However, progress in this area has been hampered by the complexity of the antigens associated with ovarian tumors and the lack of standardized, well-characterized sources of antigens or target cells. Enzymes, especially those involved in glycoprotein biosynthesis, (eg, glycoprotein:glycosyltransferases and glycosidase) have been explored as possible early biochemical indicators of ovarian neoplasia. A serum specific deficiency of alpha-L-fucosidase has been found in patients with ovarian cancers. Of all the glycoprotein:glycosyltransferases studied, galactosyltransferase has been found to be the best enzyme marker for ovarian adenocarcinoma. The determination of serum levels of this enzyme reflected the clinical status of the patient with respect of tumor progression as well as tumor burden. Recently, assay of a phosphodiesterase, which specifically hydrolyzes cytidine 5'-monophospho-N-acetylneuraminic acid, has been found promising in the detection and management of patients with ovarian cancer.
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PMID:Tumor markers for ovarian cancer. 9 53

We determined the relative distribution of tissue plasminogen activator (TPA) antigen, urokinase-type PA antigen, PA inhibitor activity, and fibronectin levels in lysates of human granulosa cells (GC) and the respective follicular fluid (FF) in relationship to oocyte-corona-cumulus complex morphology. In addition, FF gonadotropins were measured to investigate a possible relationship of gonadotropins to PA activity. A significant increase of TPA antigen in GC lysates of intermediate and mature oocyte-corona-cumulus complex was found when compared with immature oocyte-corona-cumulus complex. Urokinase-type plasminogen activator levels and PA inhibitor levels did not reveal any significant differences between the different groups. In FF the concentrations of PA and PA inhibitor were significantly lower than in GC lysates and showed no significant difference between the oocyte-corona-cumulus complex groups. The concentration of fibronectin was significantly elevated in GC lysates of mature follicles. The marked increase of TPA in human GC during oocyte maturation showed a positive correlation with the increase of FF follicle-stimulating hormone and beta-human chorionic gonadotropin in the group of mature oocyte-corona-cumulus complex. The data obtained suggest that in man TPA is the predominant PA involved in the process leading to follicular rupture.
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PMID:Plasminogen activators, plasminogen activator inhibitor, and fibronectin in human granulosa cells and follicular fluid related to oocyte maturation and intrafollicular gonadotropin levels. 224 29

To assess the role of inhibitors of proteolytic enzymes, such as plasminogen activator (PA) and collagenase in the ovulatory process, inhibitor activity and mRNA levels were examined in periovulatory rat and human ovaries. In the rat, immature animals received 20 IU of pregnant mare serum gonadotropin (PMSG) followed 52 h later by 10 IU of hCG. Ovaries were removed at intervals from 0 to 20 h after human chorionic gonadotropin (hCG) administration. Inhibitor activity for metalloproteinases, such as collagenase, increased from 60.5 +/- 4.1 inhibitor units/ovary at 0 h (i.e., time of hCG treatment) to a maximum of 218.2 +/- 11.4 units/ovary at 8 h after hCG before decreasing at 12 h (time of ovulation) and 20 h (122.2 +/- 7.9 and 71.6 +/- 8.1 units/ovary, respectively). Human follicular fluid and granulosa cells were obtained from preovulatory follicles of patients in our in vitro fertilization program. Metalloproteinase inhibitor activity was evaluated in follicular fluid as well as the levels of PA and PA inhibitor (PAI) mRNA by Northern analysis. Increasing metalloproteinase inhibitor activity was positively correlated with follicular levels of estradiol (p less than 0.001) and progesterone (p less than 0.02, N = 26). Chromatographic separation of follicular fluid resulted in two peaks of metalloproteinase inhibitor activity. The large molecular weight (MW) inhibitor had an approximate size of 700 kilodaltons (kDa) and may represent alpha 2-macroglobulin, a serum-derived inhibitor. The small MW inhibitor shared many of the characteristics of tissue-derived inhibitors of metalloproteinases. Partial purification of the small MW inhibitor by Concanavalin A-Sepharose and Heparin-Sepharose chromatography demonstrated the inhibitor to be a glycoprotein with an approximate MW = 28-29 K. Northern analysis of human granulosa cell total RNA from preovulatory follicles showed little or no detectable tissue-type PA or urokinase-type PA mRNA. In contrast, two species of PA inhibitor type-1 mRNA were detected in relative abundance. The present findings demonstrate the presence of proteolytic inhibitors in periovulatory ovaries of the rat and human. These ovarian inhibitors may play a role in regulating connective tissue remodeling during follicular rupture.
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PMID:The role of ovarian proteases and their inhibitors in ovulation. 255 99

Two types of plasminogen activator (tissue-type, tPA; urokinase-type, uPA) have been demonstrated in ovarian granulosa cells, but only tPA activity was found in denuded oocytes. Immature rats were treated subcutaneously with 20 IU pregnant mare's serum gonadotropin (PMSG) to stimulate follicle maturation, followed 2 days later by an injection of 10 IU human chorionic gonadotropin (hCG) to induce ovulation. Cellular plasminogen activator activities were determined by sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis followed by a fibrin-overlay technique. Cumulus-oocyte complexes from rats before and after PMSG treatment contained low amounts of tPA, but not uPA, activity. After hCG treatment, tPA activity showed a time-dependent increase, reaching a maximum at 24 h after injection. At 12 and 24 h after hCG treatment, uPA activity was also detected. The appearance of high molecular weight lysis zones further suggested the formation of plasminogen activator-inhibitor complexes. Morphological analysis indicated that the increases in oocyte tPA activity were correlated with the extent of cumulus cell expansion and dispersion. In denuded oocytes, tPA activity also progressively increased during the periovulatory period to a maximum at 24 h after hCG treatment. In contrast, neither uPA activity nor activator-inhibitor complex was detected. Secretion of the proteases was measured in the conditioned media of cumulus-oocyte complexes cultured for 24 h in vitro. Substantial increases in tPA release were found in complexes obtained at 8 and 12 h after hCG injection, with lower secretion from complexes obtained at 24 h after hCG treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Plasminogen activator activity in cumulus-oocyte complexes of gonadotropin-treated rats during the periovulatory period. 310 10

Cultured human cytotrophoblasts synthesize and secrete urokinase-type plasminogen activator (uPA) during the first 24 h of culture, but secretion declines during the subsequent day. In contrast, synthesis and secretion of fibronectin increases during the 2 days of culture. The levels of uPA mRNA parallel the changes in synthesis and secretion of uPA. Treatment of cytotrophoblasts with 8-bromo-cAMP (1.5 mM) transiently raises uPA mRNA levels and uPA secretion. This treatment reduces fibronectin mRNA levels and causes a sustained increase in beta chorionic gonadotropin mRNA content and chorionic gonadotropin secretion. We conclude that a cAMP-mediated process up-regulates uPA expression in cytotrophoblasts. However, the stimulatory effect of the cyclic nucleotide analog on uPA is transient.
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PMID:Regulation of urokinase-type plasminogen activator production by cultured human cytotrophoblasts. 330 45

Proteolytic activity generated by the plasminogen activator (PA) system has been associated with many biological processes. Using a pregnant mare serum gonadotropin (PMSG)/human chorionic gonadotropin (hCG)-induced rhesus monkey corpus luteum (CL) model, we have studied how urokinase-type plasminogen activator (uPA), tissue-type plasminogen activator (tPA), and plasminogen activator inhibitor type 1 (PAI-1), are temporally expressed in CL of rhesus monkey at the luteotropic and luteolytic periods. Slot blot analysis and in situ hybridization were performed to analyze the expression and distribution of uPA and PAI-1 messenger RNA (mRNA). Fibrin overlay was used to detect uPA and tPA activities. We found that uPA is the dominating PA in luteotropic CL in the monkey. Abundant expression of PAI-1 mRNA was detected. The highest expression of uPA and PAI-1 mRNA was observed at the luteotropic period, while their expression decreased approximately 50% at early luteal regression defined by considerably decreased serum progesterone levels, and remained at very low levels at the late stage of luteal regression. We also observed an increased tPA activity at the time of luteal regression. Moreover, the exogenous tPA could inhibit the progesterone production in cultured luteal cells from 13-day-old monkey CL. We also used LH receptor mRNA expression as a mark for the luteal phases. A highly expressed, evenly distributed LH receptor mRNA was detected in CL during the luteotropic phase, while its expression decreased at day 13 coinciding with the reduction of progesterone production. We conclude that proteolysis mediated by uPA and regulated by PAI-1 may play a role in the luteal maintenance, while tPA may participate in the luteal regression in the rhesus monkey.
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PMID:Temporal expression of urokinase type plasminogen activator, tissue type plasminogen activator, plasminogen activator inhibitor type 1 in rhesus monkey corpus luteum during the luteal maintenance and regression. 940 56

Low-pressure ion-exchange chromatography was used for sequential isolation of chorionic gonadotropin and urokinase (EC 3.4.99.26) from urine of pregnant women. Theoretical analysis of electrostatic interactions of protein macromolecules with the sorptive surface of a carboxylic cation exchanger was performed. This analysis allowed us to optimize the pH values for selective sorption and reversible desorption of the target component on a cation exchanger with a selected acidity of functional groups. The use of carboxylic cation exchangers KM-2p and Biokarb-GM allowed us to obtain the preparations with purity not inferior to commercially available preparations.
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PMID:[Preparative isolation of gonadotropin and urokinase on carboxylic cation exchangers]. 1054 78

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a reproductive toxicant and endocrine disrupter that is known to block ovulation. This study was designed to investigate alterations in relevant ovarian genes that may be involved in the blockage of ovulation by TCDD in immature intact rats primed with equine chorionic gonadotropin (eCG). In this ovulation model, rats were given either 32 microg/kg TCDD or corn oil by gavage on 25 days of age. The next day, eCG (5 IU) was injected subcutaneously (s.c.) to stimulate follicular development. Ovulation occurs 72 h after administration of eCG in controls of this model. TCDD blocked ovulation at the expected time and also reduced both ovarian and body weights. At 72 h after eCG (the morning after expected ovulation), TCDD did not alter significantly serum concentrations of progesterone (P4) and androstenedione (A4). However, estradiol (E2) was significantly higher at 72 h after eCG in TCDD-treated rats when compared with controls. Western blots revealed that ovarian CYP1A1 was induced by TCDD. In addition, the aryl hydrocarbon receptor (AhR) and AhR nuclear translocator (ARNT) were down- and up-regulated by TCDD, respectively, indicating that AhR-mediated signal transduction was altered in the ovary. Ovarian estrogen receptor (ER)alpha, ER beta and progesterone receptor (PR) were not altered significantly by TCDD, but ovarian glucocorticoid receptor (GR) was increased at 24h after TCDD and decreased at 72 h after eCG when compared with controls. TCDD induced the early appearance of ovarian plasminogen activator inhibitor type-1 (PAI-1), plasminogen activator inhibitor type-2 (PAI-2), urokinase plasminogen activator (uPA), and tissue plasminogen activator (tPA) at 24h after dosing when compared with controls. On the morning after ovulation (72 h after eCG), no significant differences between control and TCDD-treated rats were observed except that TCDD had still increased tPA and decreased PAI-2 when compared with controls. Interestingly, ovarian COX-2 was induced on the morning after ovulation (72 h after eCG) in controls, but was greatly inhibited in TCDD-treated rats at that time. On the other hand, COX-1 was constitutively expressed throughout the ovulatory period and remained unaffected by TCDD. Immunolocalization of COX-2 in the ovary revealed that TCDD inhibited COX-2 expression in the granulosa cell layer when assessed in the morning of expected ovulation. In conclusion, AhR signaling is activated in the ovary by TCDD and inhibition of COX-2 appeared to be a critical step in the TCDD blockage of ovulation because blockage or reduction of COX-2 expression is well known to be associated with failure of ovulation.
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PMID:Alteration in ovarian gene expression in response to 2,3,7,8-tetrachlorodibenzo-p-dioxin: reduction of cyclooxygenase-2 in the blockage of ovulation. 1212 4

The corpus luteum (CL) is a transient endocrine organ that secretes progesterone to support early pregnancy. Using primate materials obtained from rhesus monkeys, we have in this study investigated the expression and regulation of the plasminogen activators (PAs) and PA inhibitor type 1 (PAI-1) during CL development and regression. Adult (5-7 yr old) female rhesus monkeys were treated with pregnant mare serum gonadotropin/human chorionic gonadotropin to induce ovulation and follicular luteinization. At various luteal developmental stages, CL or whole ovaries were obtained for preparing luteal cells, Northern blot, in situ hybridization, and immunohistochemistry. We demonstrated that luteal cells from the rhesus monkey were able to produce both tissue type PA (tPA) and urokinase type PA, as well as the physiological PAI-1. During luteal development in the monkey, urokinase type PA was the major PA species taking part in the active angiogenesis and tissue remodeling processes in the forming CL. However, the mRNA as well as the enzymatic activity levels of tPA increased dramatically in monkey CL with the advent of luteolysis. This change of tPA levels was in a temporal coordination with the regulation of PAI-1 expression, resulting in an increased tPA activity at the initiation of luteolysis. Therefore, we suggest that tPA might be a luteolytic factor to the monkey CL. A PAI-1 modulated tPA activity might be important for the initiation of luteolysis in the monkey. In addition, we have also demonstrated that the expression of steroidogenic acute regulatory protein in the monkey CL was in accordance with the changes of progesterone production, suggesting that steroidogenic acute regulatory protein expression may be considered as a reliable marker for CL function in primates.
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PMID:Expression and regulation of plasminogen activators, plasminogen activator inhibitor type-1, and steroidogenic acute regulatory protein in the rhesus monkey corpus luteum. 1286 43

Extracellular matrix remodeling occurs during ovarian follicular development, mediated by plasminogen activators (PAs) and PA inhibitors including protease nexin-1 (PN-1). In the present study we measured expression/activity of the PA system in bovine follicles at different stages of development by timed collection of ovaries during the first follicular wave and during the periovulatory period, and in follicles collected from an abattoir. The abundance of mRNA encoding PN-1, tissue-type PA (tPA), urokinase (uPA) and PA inhibitor-1 (PAI-1) were initially upregulated by human chorionic gonadotropin (hCG) in bovine preovulatory follicular wall homogenates. PN-1, PAI-1 and tPA mRNA expression then decreased near the expected time of ovulation, whereas uPA mRNA levels remained high. PN-1 concentration in follicular fluid (FF) decreased and reached the lowest level at the time of ovulation, whereas plasmin activity in FF increased significantly after hCG. Follicles collected from the abattoir were classified as non-atretic, early-atretic or atretic based on FF estradiol and progesterone content: PN-1 protein levels in FF were significantly higher in non-atretic than in atretic follicles, and plasmin activity was correspondingly higher in the atretic follicles. No changes in PN-1 levels in FF were observed during the growth of pre-deviation follicles early in a follicular wave. These results indicate that PN-1 may be involved in the process of atresia in non-ovulatory dominant follicles and the prevention of precocious proteolysis in periovulatory follicles.
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PMID:Expression of protease nexin-1 and plasminogen activators during follicular growth and the periovulatory period in cattle. 1638 16


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