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)

The cyclic secretion of plasminogen activator (PA) by Sertoli cells in stages VII and VIII of the rat seminiferous epithelial cycle is influenced by hormones and adjacent spermatogenic cells. To understand this interaction more in detail, we have analyzed the effects of FSH, (Bu)2cAMP, testosterone, insulin, and retinoic acid (RA) on staged seminiferous tubule segments in vitro. FSH stimulated stages VIIcd to XI of the cycle; similar results were obtained with (BU)2cAMP. RA stimulated PA secretion in stages I-VIIab, but testosterone and insulin had no effect in any stage. The secreted PA was mainly of the urokinase type, although small amounts of the tissue-type PA were found after stimulation by FSH and cAMP. These results suggest that spermatogenic cells modify the responsiveness of Sertoli cells to hormonal stimulation. Stages I-VIIab are sensitive to stimulation by RA whereas stages VIIcd-XI are preferentially stimulated by FSH and (Bu)2cAMP.
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PMID:Stage-specific regulation of plasminogen activator secretion in the rat seminiferous epithelium. 302 24

It is well established that rat ovarian granulosa cells produce tissue plasminogen activator (tPA). The synthesis and secretion of the enzyme are induced by gonadotropins, and correlate well with the time of follicular rupture in vivo. We have found that in contrast, mouse granulosa cells produce a different form of plasminogen activator, the urokinase-type (uPA). As with tPA synthesis in the rat, uPA production by mouse granulosa cells is induced by gonadotropins, dibutyryl cAMP, and prostaglandin E2. However, dexamethasone, a drug which has no effect on tPA synthesis in rat cells inhibits uPA synthesis in the mouse. Results of these determinations made in cell culture were corroborated by examining follicular fluid, which is secreted in vivo predominantly by granulosa cells, from stimulated rat and mouse ovarian follicles. Rat follicular fluid contained only tPA, and mouse follicular fluid only uPA, indicating that in vivo, granulosa cells from the two species are secreting different enzymes. The difference in the type of plasminogen activator produced by the rat and mouse granulosa cells was confirmed at the messenger RNA level. After hormone stimulation, only tPA mRNA was present in rat cells, whereas only uPA mRNA was found in mouse cells. Furthermore, the regulation of uPA levels in mouse cells occurs via transient modulation of steady-state levels of mRNA, a pattern similar to that seen with tPA in rat cells.
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PMID:Mouse ovarian granulosa cells produce urokinase-type plasminogen activator, whereas the corresponding rat cells produce tissue-type plasminogen activator. 304 Jul 74

FSH and GnRH both stimulate rat granulosa cells to produce tissue-type plasminogen activator (tPA). We have studied the molecular mechanisms involved in the action of these hormones by measuring tPA mRNA levels in primary cultures of rat granulosa cells. When granulosa cells were cultured in the presence of FSH or GnRH the level of tPA mRNA was increased 20- and 12-fold, respectively. The induction of tPA mRNA by FSH and GnRH was additive and the kinetics of induction differed. The effect of FSH could be mimicked by bromo-cAMP or forskolin, and was drastically enhanced by cotreatment with the phosphodiesterase inhibitor 1-methyl-3-isobutylxanthine. These findings are consistent with the notion that FSH mediates its effect through the protein kinase A pathway. GnRH is believed to augment phospholipid turnover in granulosa cells, leading to the activation of the protein kinase C pathway. Like GnRH, the protein kinase C activator phorbol myristate acetate also induced tPA mRNA in granulosa cells. In the presence of the protein synthesis inhibitor, cycloheximide, FSH-stimulated tPA message levels were enhanced by 30-fold, revealing superinduction of tPA mRNA levels by this pathway. In contrast the induction of tPA mRNA by GnRH was inhibited by cycloheximide indicating that the synthesis of an intermediate protein is required for the GnRH effect. Our data suggest that FSH and GnRH increase the tPA mRNA levels by two distinct pathways in cultured granulosa cells, providing a model system for studying the hormonal regulation of tPA gene expression.
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PMID:Hormonal regulation of tissue-type plasminogen activator messenger ribonucleic acid levels in rat granulosa cells: mechanisms of induction by follicle-stimulating hormone and gonadotropin releasing hormone. 313 93

As stated earlier, the mammalian ovary maintains the continuous development of follicles, but only a few are selected to ovulate and form corpora lutea. These processes are regulated primarily by the gonadotropins and involve specific, sequential changes in the function of theca cells and granulosa cells. Data from recent studies (summarized in Figure 3) show that specific genes are turned on or off at different stages of follicular growth in response to estradiol and different amounts of gonadotropins and cAMP. For example, mRNA for RII51 in granulosa cells and theca cells increases in association with small increased in cAMP but is markedly reduced by the LH surge and high cAMP. The content of mRNA for other kinase subunits, RI and C alpha, show little or no change during similar hormonal changes. In theca cells, mRNA for 17 alpha-hydroxylase increased and decreased in a manner similar to that for RII51. In contrast, levels of mRNA for P450scc increased only gradually in follicles but were markedly increased by the LH surge and high concentrations of cAMP and then appeared to be constitutively expressed in rat corpora lutea in a cAMP-independent manner. PGS and t-PA appear to follow yet another pattern: rapid induction by the LH surge followed by a rapid decline in association with ovulation. One major task for reproductive endocrinologists and molecular biologists now is to determine how low and high concentrations of cAMP act to turn on and turn off the expression of these specific genes at specific times during follicular maturation. A working model of the molecular events occurring in theca and granulosa cells of PO follicles is shown in Figure 4. LH acts on theca cells via cAMP ro regulate both P450scc and P450(17) alpha mRNA levels, leading to increased biosynthesis of androstenedione. The mechanisms by which cAMP acts in theca cells remain to be determined but appear to involve an increase in the content of RII51, P450scc, and P450(17) alpha. In granulosa cells, androstenedione is converted to estradiol by the aromatase P450 enzyme system. Estradiol, in turn, binds to estradiol receptors present in these cells and may thereby regulate gene expression. However, despite the presence of estradiol and estradiol receptors, little or no effect of estradiol is observed unless FSH acts via the FSH receptor to increase intracellular concentrations of cAMP. In a manner not yet understood, cAMP appears to enhance the actions of estradiol.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Molecular aspects of hormone action in ovarian follicular development, ovulation, and luteinization. 328

Peptides corresponding to the amino-terminal region of the parathyroid hormone-related protein (PTHrP) of humoral hypercalcemia of malignancy were synthesized. A 34-amino acid peptide, PTHrP(1-34), was two to four times more potent than bovine or human PTH(1-34) in bioassays promoting the formation of adenosine 3',5'-monophosphate (cAMP) and plasminogen activator activity in osteogenic sarcoma cells and adenylate cyclase activity in chick kidney membranes. Like parathyroid hormone itself, in which the activity resides in the first 34 residues, PTHrP peptides of less than 30 residues from the amino terminus showed substantially reduced activity. PTHrP(1-34) had only 6% of the potency of bovine PTH(1-34) in promoting bone resorption in vitro. PTHrP(1-34) strongly promoted the excretion of cAMP and phosphorus and reduced the excretion of calcium in the isolated, perfused rat kidney consistent with the symptoms seen in malignant hypercalcemia.
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PMID:Parathyroid hormone-related protein of malignancy: active synthetic fragments. 368 95

Tumor promoting phorbol esters and mezerein strongly induced plasminogen activator (urokinase, uPA) synthesis in porcine kidney cell cultures (LLC-PK1). Induction was due to increased uPA-mRNA levels which rose from 10 to 300 molecules/cell within 2 h of exposure to 16 nM phorbol myristate acetate. We have compared the action of tumor promoters with that of 8-bromo-cAMP, another potent inducer of uPA; the similarities between the two kinds of induction were: both involved transcriptional activation of the uPA gene; both were rapid in onset, changes in transcription rate being detectable within 10-20 min; the initial rates of transcription and uPA-mRNA accumulation were substantial and in the same order of magnitude; neither class of inducer required protein synthesis to stimulate uPA transcription. The main contrast between the two types of agents was that the uPA response to tumor promoters was transient whereas that to cAMP compounds was sustained: cultures rapidly lost their response to tumor promoters within 2 h after initial exposure while retaining responsiveness to cAMP-related agents. The cells developed a specific drug-induced desensitization which was slowly reversed after tumor promoters were removed from the culture medium. Since protein kinase C is now well established as the receptor for phorbol-derived and several other tumor promoters it will be of interest to determine whether desensitization occurs at the level of receptor.
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PMID:Induction and desensitization of plasminogen activator gene expression by tumor promoters. 386 68

We have found that ovulated mouse and rat oocytes contain tissue-type plasminogen activator (PA). Primary oocytes isolated from ovaries did not contain the enzyme. During spontaneous meiotic maturation in vitro, tissue-type PA became detectable 5 hr after germinal vesicle breakdown. Induction of tissue-type PA activity was blocked by dibutyryl-cAMP or isobutylmethyl-xanthine as well as by cycloheximide, but not by actinomycin D or alpha-amanitin. These results suggest that tissue-type PA mRNA is present in primary oocytes, and that translation of this mRNA is triggered upon resumption of meiotic maturation. Tissue-type PA catalyzed proteolysis around live secondary oocytes and fertilized eggs, indicating secretion of the enzyme. Unlike secondary oocytes, fertilized eggs denuded of their zona pellucida no longer contained the enzyme, suggesting that tissue-type PA production stops at or around fertilization, and that the bulk of the enzyme is secreted at this time.
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PMID:Plasminogen activator in mouse and rat oocytes: induction during meiotic maturation. 393 23

We have isolated cDNA and genomic clones coding for porcine plasminogen activator (urokinase, uPA). The cDNA is 2375 nucleotides long: it consists of a 5'-non-coding region (104 nucleotides), an open reading frame of 1329 nucleotides, and 3'-non-coding region of 942 nucleotides apart from the poly A tail. The genomic segment corresponding to the transcribed sequence is 5.85 kb long; it is composed of 11 exons and 10 introns. The 5'-flanking genomic region contains a number of sequences of potential regulatory significance, including possible hormone receptor binding sites and a sequence which we tentatively propose may be involved in activation of transcription by cAMP. The full sequence of both cDNA and genomic clones, the latter including 1.3 kb of flanking region, is presented and discussed, and the deduced amino acid sequence compared with that of human uPA.
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PMID:cDNA and gene nucleotide sequence of porcine plasminogen activator. 609 32

Sertoli cells in primary cultures produce plasminogen activator activity, and release it into the medium at rates greatly influenced by a variety of factors, including cell density, the presence of hormones, incubation temperature and duration of culture. In Sertoli cells maintained in culture in the presence of dibutyryl cAMP, the amounts of plasminogen activator activity secreted per cells were maximal at cell densities up to 2.5 microgram DNA/cm2 (350 units/microgram cell DNA), and declined to 40 units/microgran cell DNA at a density of 22 micrograms DNA/cm2. Concentrations of follicle-stimulating hormone (FSH) required to elicit half-maximal stimulation of the production of plasminogen activator activity were 0.37 micrograms/ml for oFSH-NIH S12 and 8 ng/ml for the more purified of SH-S1528C2. The ED50 for dibutyryl cAMP was found to be 0.08 mM. Addition of an inhibitor of phosphodiesterase (3-isobutyl-l-methylxanthine) enhanced the formation of plasminogen activator by cells cultured in the presence of FSH. Addition to the culture medium of testosterone, epidermal growth factor, insulin, human chorionic gonadotropin or prostaglandins (E1, E2 or F1 alpha) did not result in increased production of PA activity by Sertoli cells. Cells in culture for as long as 14 days remained responsive to FSH or dibutyryl cAMP. Increases in cellular levels of plasminogen activator became evident within 2-4 after addition of either FSH or dibutyryl cAMP to the medium. The stimulation of FSH or dibutyryl cAMP of the production of plasminogen activator activity was shown to be dependent upon de novo synthesis of RNA and protein. Levels of enzyme activity released by Sertoli cells maintained in culture for 48 h at 37 degrees C were approx. 50% higher than plasminogen activator released by cells cultured at 32 degrees C. The control of the production of plasminogen activator activity by Sertoli cells was discussed in relation to the control of plasminogen activator production by granulose cells, and the possible role of plasminogen activator in gonadal functions.
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PMID:The control of the synthesis and secretion of plasminogen activator by rat sertoli cells in culture. 617 77

Incubation of rat hepatoma cells with cAMP derivatives stimulates cell-associated plasminogen activator activity 8- to 22-fold and extracellular plasminogen activator activity 30- to 1300-fold. This time- and concentration-dependent increase is enhanced by phosphodiesterase inhibitors. Dexamethasone, a synthetic glucocorticoid, decreases the plasminogen activator activity of these cells, probably through induction of an inhibitor. Paradoxically, dexamethasone, added simultaneously with cAMP derivatives causes a further 4-fold enhancement of the cAMP-mediated stimulation of plasminogen activator activity. Dexamethasone also alters the time course of cAMP-mediated enhancement of plasminogen activator activity: increased protease activity is detected at 4 hr in cells incubated with 8-bromoadenosine-3':5'-cyclic monophosphoric acid and 1-methyl-3-isobutylxanthine but not until 12 hr in cells incubated with dexamethasone as well. Glucocorticoids thus exert two separate and opposite effects on plasminogen activator activity: induction of an inhibitor and amplification of cyclic nucleotide action. Although permissive and synergistic effects of dexamethasone on cyclic nucleotide action have been reported previously, glucocorticoid regulation of plasminogen activator activity is unique in that the amplification of cyclic nucleotide effects by dexamethasone opposes its regulatory action toward a specific enzyme.
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PMID:Paradoxical effects of glucocorticoids on regulation of plasminogen activator activity of rat hepatoma cells. 617 95


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