Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Y1 mouse adrenal tumor cells and mutants of Y1 cells (Kin 2 and Kin 8), with defects in regulatory subunit of type 1 protein kinase (R1), were assayed for steroid, growth, and plasminogen activator after application of the tumor promoter 12-O-Tetradecanoylphorbol-13-acetate (TPA). TPA, like ACTH, caused an increase in steroid production and a decrease in growth in Y1 cells. The effects on steroidogenesis were diminished in Kin 2 and markedly diminished in Kin 8. TPA induced plasminogen activator in Y1 but not Kin 2 or Kin 8 while ACTH induced the enzyme in both Y1 and Kin 2 but not Kin 8. TPA did not produce a measurable increase in cyclic nucleotides in Y1 cells. Unlike Cytochalasin E, another agent that causes steroidogenesis without changes in cyclic AMP concentration, TPA and ACTH did not require serum for its effect on steroid production. Cytochalasin E also caused induction of plasminogen activation in Y1, but not in Kin 2 or Kin 8 cells. TPA however produced growth inhibition in both mutant cell types while ACTH produced a progressively diminishing growth inhibitory effect in Kin 2 and Kin 8. The results suggest that a portion of TPA action on Y1 cells requires R1.
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PMID:Action of 12-O-tetradecanoylphorbol-13-acetate on Y1 adrenal cells apparently requires the regulatory subunit of type 1 cyclic AMP dependent protein kinase. 610 Sep 78

The effects of 12-O-tetradecanoylphorbol-13-acetate (TPA) on the sarc protein kinase of normal chick embryo fibroblasts (CEF) and of the src kinase of cells transformed by a temperature-sensitive mutant of avian sarcoma virus (CEF-tsASV) were studied and compared with the known effects of TPA on cell morphology and plasminogen activator (PA) activity. One hr after the addition of TPA to normal CEF, there was a 3- to 8-fold stimulation of kinase activity when compared to control cultures; during the subsequent 24 hr, TPA produced less than a 2-fold stimulation. Although TPA induced levels of PA in CEF which were equivalent to those produced by cEF-tsASV grown at 36 degrees, the latter cells contained much higher levels of kinase activity than those of CEF plus TPA. In addition, TPA failed to enhance the kinase activity of CEF-tsASV at either 36 degrees or 40 degrees, even though at both temperatures TPA induced morphological changes and markedly enhanced PA activity. These results suggest that the effects of TPA on morphology and PA are not due to an effect on these protein kinases.
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PMID:Effect of tumor promoters on sarc gene expression in normal and transformed chick embryo fibroblasts. 626 Mar 44

Two temperature-sensitive mutants of Fujinami sarcoma virus were isolated and characterized. Cells infected with the mutants were temperature sensitive in focus formation, colony formation, increased sugar uptake, and synthesis of plasminogen activator. The changes between transformed and nontransformed states of cultures were completely reversible by shifting the temperature. A Fujinami sarcoma virus-specific protein of 130,000 daltons, p130, was synthesized in mutant-infected cells regardless of the temperature, but the immunoprecipitates of p130 from extracts of infected cells were active in protein kinase only when cells had been incubated at the permissive temperature. These results appear to indicate that p130 is the transforming protein of Fujinami sarcoma virus, and that its protein kinase activity plays a crucial role in cell transformation by this virus.
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PMID:Mutants of Fujinami sarcoma virus which are temperature sensitive for cellular transformation and protein kinase activity. 626 8

Fifteen transformation defective sensitive mutants of Rous sarcoma virus have been investigated to see if the expression of the pp60src-associated protein kinase activity correlated with other parameters of transformation such as altered growth control, morphological changes, increased hexose transport, and increased plasminogen activator protease synthesis. The expression of a protein kinase activity paralleled or preceded the onset of other parameters of transformation with but one exception: altered control of cell growth. The stability of the pp60src molecule in mutant-infected cells at the nonpermissive temperature was investigated with the finding that mutant pp60src did not show an increased turnover at the nonpermissive temperature as compared to wild type virus pp60src. Furthermore, it could be shown that pre-existing pp60src in mutant-infected cells maintained at the non-permissive temperature became activated after temperature shift to the permissive temperature. Temperature shift performed under conditions of inhibition of new protein synthesis with cycloheximide, puromycin, or emetine was followed by greatly increased protein kinase activity, and a parallel phosphorylation of pp60src itself in tyrosine residues. Morphological features of transformation could be demonstrated likewise under conditions of inhibition of protein synthesis.
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PMID:In vitro transformation with Rous sarcoma virus and the pp60src-associated protein kinase. 626 96

Plasminogen activators are highly selective proteases that activate the proenzyme plasminogen to the general protease, plasmin. We studied a porcine kidney cell line, originally isolated as a high producer of plasminogen activator, in which activities of cellular adenylate cyclase and cAMP-dependent protein kinase are increased in response to calcitonin. We found that salmon calcitonin, in the concentration range 0.03-300 nM, increased plasminogen activator production up to approximately 1,000-fold and concurrently inhibited cell multiplication; both of these effects were reversible. Human calcitonin was approximately 0.01 times as potent as salmon calcitonin, corresponding to potency differences observed in other biological systems. Plasminogen activator production was also stimulated by other agents that raise cellular cAMP levels such as cholera toxin, phosphodiesterase inhibitors, and vasopressin, but not to the same extent as by calcitonins. The rapidity and sensitivity of the plasminogen activator determination and other cellular responses may make it possible in the future to use this cell stain in a convenient bioassay for calcitonins and their analogues.
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PMID:Calcitonin stimulates plasminogen activator in porcine renal tubular cells: LLC-PK1. 627 91

Expression of the src gene of Rous sarcoma virus in chicken embryo neuroretinal cells results in morphological transformation and sustained proliferation of this normally resting cell population. PA101 and PA104 are two mutants of Rous sarcoma virus which induce neuroretinal cell proliferation in the absence of morphological transformation. Their mitogenic property is temperature sensitive, and they both encode p60src proteins with low kinase activity. To study the role of the mitogenic function and protein kinase activity of p60src in tumorigenesis, we investigated the oncogenicity of PA101 and PA104. Both mutants were less tumorigenic than wild-type virus when injected into chicks. Tumorigenicity was further assayed by inoculating infected chicken embryo fibroblasts and neuroretinal cells onto the chorioallantoid membrane of embryonated duck eggs. This system provides a nonpermissive and immunodeficient environment for xenogenic cell grafting and allows the study of cell tumorigenicity within a temperature range of 37 to 39.5 degrees C. Chicken embryo fibroblasts and neuroretinal cells infected with PA101 were as tumorigenic as wild type-infected cells at 37 degrees C, but tumor development was significantly reduced at 39.5 degrees C. In contrast, both cell types infected with PA104 displayed sharply reduced tumorigenicity. Cell cultures derived from PA101 tumors induced on the chorioallantoid membrane were similar to the corresponding cells maintained in vitro in terms of morphology, production of plasminogen activator, relative amounts of phosphotyrosine in total cellular proteins, and phosphorylation of 34,000-molecular-weight protein. These results indicate that the expression of the mitogenic function of src does not account per se for cell tumorigenicity and that tumor formation is compatible with low levels of p60src protein kinase activity.
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PMID:Role of the mitogenic property and kinase activity of p60src in tumor formation by Rous sarcoma virus. 631 32

Retinoic acid induces the differentiation of many murine teratocarcinoma stem cell lines. To elucidate the molecular mechanism of action of retinoic acid, we have selected a series of mutants which exhibit altered differentiation responses to retinoic acid. All of the mutants display abnormal morphology following addition of 5 X 10(-7) M retinoic acid (RA) and dibutyryl cAMP. In addition, none of the mutants are resistant to the cytotoxic effects of higher concentrations of retinoic acid (greater than 75 microM). After the addition of retinoic acid, one mutant, RA-3-10, does not differentiate by any of the biochemical criteria we have used; this mutant also possesses less than 5% of the wild type level of cellular retinoic acid binding protein (CRABP). Other mutants, such as RA-3-3, RA-3-4, and RA-5-1, contain the same amount of CRABP as wild type F9 cells. However, the mutants RA-3-3 and RA-3-4 exhibit lower levels of plasminogen activator activity, and RA-3-4 also exhibits only 10-20% of the wild type synthesis and secretion of laminin and collagen IV following treatment with RA. After RA treatment of the mutant RA-5-1, laminin and collagen IV are synthesized and secreted at reduced rates relative to wild type cells, and the secreted collagen IV has a lower molecular weight than that of wild type; this suggests that RA-5-1 cells have a mutation in one of the enzymes responsible for post-translational modification of collagen IV. None of the mutants tested exhibits alterations in either cytosolic or membrane bound cAMP-dependent protein kinase activity. These studies provide genetic evidence that the CRABP is required for the differentiation of F9 teratocarcinoma stem cells by retinoic acid. However, even in the presence of CRABP, other types of alterations, such as synthesis of collagen IV with an abnormal molecular weight, appear to cause alterations in the differentiation response of cells to retinoic acid.
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PMID:Selection and characterization of F9 teratocarcinoma stem cell mutants with altered responses to retinoic acid. 632 55

In addition to its intra-cellular functions, cAMP-dependent protein kinase (PKA) may well have an extra-cellular regulatory role in blood. This suggestion is based on the following experimental findings: (a) Physiological stimulation of blood platelets brings about a specific release of PKA, together with its co-substrates ATP and Mg++; (b) In human serum, an endogenous phosphorylation of one protein (p75, M(r) 75 kDa) occurs; this phosphorylation is enhanced by addition of cAMP and blocked by the Walsh-Krebs specific PKA inhibitor; (c) No endogenous phosphorylation of p75 occurs in human plasma devoid of platelets, but the selective labeling of p75 can be reproduced by adding to plasma the pure catalytic subunit of PKA; (d) p75 was shown to be vitronectin (V), a multifunctional protein implicated in processes associated with platelet activation, and thus a protein whose function may require modulation for control; (e) The phosphorylation of vitronectin occurs at one site (Ser378) which, at physiological pH, is buried in its two-chain form (V65 + 10) but it becomes 'exposed' in the presence of glycosaminoglycans (GAGs) e.g. heparin or heparan sulfate. Such a transconformation may be used for targeting the PKA phosphorylation to vitronectin molecules bound to GAGs, for example in the extracellular matrix or on cell surfaces; (f) From the biochemical point of view (Km values and physiological concentrations) the phosphorylation of vitronectin can take place at the locus of a hemostatic event; (g) The phosphorylation of Ser378 in vitronectin alters its function, since it significantly reduces its ability to bind the inhibitor-1 of plasminogen activator(s) (PAI-1).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Evidence for an extra-cellular function for protein kinase A. 752 49

Migration of astrocytes is thought to play a role in nerve regeneration and to be mediated, at least in part, by inflammation-associated cytokines. Plasminogen activators are secreted proteases that function in fibrinolysis and participate in cellular migration and invasion and, in some cases, are modulated by cytokines. Here, we show that two cytokines, tumor necrosis factor-alpha and interleukin-1 beta, can modulate plasminogen activation in astrocytes, each causing 90% reduction of total plasminogen activator activity. Direct and reverse zymography indicated that this reduction resulted from two simultaneous events, a pronounced decrease in tissue-type plasminogen activator activity and an induction of plasminogen activator inhibitor-1. Northern hybridization analysis indicated a 30-fold increase of the steady-state level of plasminogen activator inhibitor-1 mRNA following treatment with each of the two cytokines. Both of the cytokine-induced effects could be blocked by cycloheximide or actinomycin D. When signal transduction pathways were blocked, the results indicated the involvement of reduction in cyclic AMP levels, protein kinase activity, and arachidonic metabolites of the lipoxygenase pathway. The results thus show that the two cytokines reduce the ability of astrocytes to conduct fibrinolysis and extracellular proteolysis, and suggest that the effect of these cytokines on members of the plasminogen activation system is through a common signal transduction pathway.
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PMID:Components of the plasminogen activator system in astrocytes are modulated by tumor necrosis factor-alpha and interleukin-1 beta through similar signal transduction pathways. 756 46

This study was undertaken to investigate, in freshly isolated rat Sertoli cells, the physiological function of the type I and type II cyclic adenosine monophosphate (cAMP)-dependent protein kinase isozymes in tissue-type plasminogen activator secretion and the regulation of this cAMP process by follicle-stimulating hormone (FSH). Follicle-stimulating hormone-induced tissue-type plasminogen activator secretion depends upon intracellular cAMP levels. The changes in cAMP amounts required to activate maximally the tissue-type plasminogen activator secretion are extremely small, a cAMP threshold having to be reached for triggering the tissue-type plasminogen activator output. Intact Sertoli cells were incubated with combinations of cAMP analogs specific for each cAMP-dependent protein kinase type and complementary in their cAMP binding site on the cAMP-dependent protein kinase regulatory subunits: 8-aminohexylamino-cAMP = type 1, site 1; 8-thiomethyl-cAMP = type II, site 1 and N6-benzoyl-cAMP = types I/II, site 2. This allowed us to activate selectively each cAMP-dependent protein kinase type in a synergistic manner and then to evaluate their respective influence in the specific tissue-type plasminogen activator response. We establish that both of the cAMP-dependent protein kinase types are present and functional; the activity of the type I isozyme is preponderant (60%) in the cAMP-dependent tissue-type plasminogen activator secretion. Likewise, when these cAMP analogs were coupled with endogenously generated cAMP by FSH or forskolin, both of the cAMP-dependent protein kinase types were involved in the tissue-type plasminogen activator production.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Involvement of cyclic adenosine monophosphate-dependent protein kinase isozymes in tissue plasminogen activator secretion by rat Sertoli cells stimulated with follicle-stimulating hormone in vitro. 768 8


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