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)

Agents that can arrest cellular proliferation are now providing insights into mechanisms of growth factor action and how this action may be controlled. It is shown here that the macrophage activating agents tumor necrosis factor-alpha (TNF alpha), interferon-gamma (IFN gamma), and lipopolysaccharide (LPS) can maximally inhibit colony stimulating factor-1 (CSF-1)-induced, murine bone marrow-derived macrophage (BMM) DNA synthesis even when added 8-12 h after the growth factor, a period coinciding with the G1/S-phase border of the BMM cell cycle. This inhibition was independent of autocrine PGE2 production or increased cAMP levels. In order to compare the mode of action of these agents, their effects on a number of other BMM responses in the absence or presence of CSF-1 were examined. All three agents stimulated BMM protein synthesis; TNF alpha and LPS, but not IFN gamma, stimulated BMM Na+/H+ exchange and Na+,K(+)-ATPase activities, as well as c-fos mRNA levels. IFN gamma did not inhibit the CSF-1-induced Na+,K(+)-ATPase activity. TNF alpha and LPS inhibited both CSF-1-stimulated urokinase-type plasminogen activator (u-PA) mRNA levels and u-PA activity in BMM, whereas IFN gamma lowered only the u-PA activity. In contrast, LPS and IFN gamma, but not TNF alpha, inhibited CSF-1-induced BMM c-myc mRNA levels, the lack of effect of TNF alpha dissociating the inhibition of DNA synthesis and decreased c-myc mRNA expression for this cytokine. These results indicate that certain biochemical responses are common to both growth factors and inhibitors of BMM DNA synthesis and that TNF alpha, IFN gamma, and LPS, even though they all have a common action in suppressing DNA synthesis, activate multiple signaling pathways in BMM, only some of which overlap or converge.
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PMID:Biochemical events accompanying macrophage activation and the inhibition of colony-stimulating factor-1-induced macrophage proliferation by tumor necrosis factor-alpha, interferon-gamma, and lipopolysaccharide. 133 37

Okadaic acid (OA), a potent mouse skin tumor promoter and inhibitor of the protein phosphatases 1 and 2A, was investigated for its effects on the expression of tumor-associated early and secondary response genes in mouse keratinocytes. Adult mice were treated topically with 12.5 nmol of OA, and the steady-state levels of various gene transcripts in the skin were determined at different times after treatment. The nuclear proto-oncogenes c-fos and c-jun are referred to as early response genes because the classical tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) induces their expression to maximal levels within 2 h after treatment. OA induced the expression of c-fos 2-72 h after treatment, with two peaks at 6 and 48 h. The steady-state level of expression of c-jun was relatively high in untreated skin, and OA induced a slight increase in its expression from 12 to 48 h after treatment. Transin and plasminogen-activator (PA) urokinase, whose induced expression peaks at least 4 h after TPA treatment, are referred to as secondary response genes. OA induced their expression more slowly than TPA. In mouse papilloma cell line 308, OA induced higher and more sustained steady-state levels of c-jun and c-fos than an equimolar dose of TPA. Transin and PA-urokinase were induced to similar levels by TPA and OA in 308 cells; however, the induction of these genes by OA was slower than induction by TPA. The existence of different patterns of induced expression of early and secondary response genes by OA and TPA suggests that these tumor promoters affect gene expression in mouse keratinocytes through different pathways.
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PMID:Okadaic acid induces the expression of both early and secondary response genes in mouse keratinocytes. 154 37

Three cancer cell lines, IMC-2, IMC-3 and IMC-4, were established from a single tumor of a patient with maxillary cancer. We examined responses to epidermal growth factor (EGF) of these 3 cell lines with regard to cell growth and tumor invasion. The growth rate of IMC-2 in nude mice was markedly faster than that of the IMC-3 and IMC-4 cell lines. Assay for invasion through fibrin gels showed significantly enhanced invasive capacity of IMC-2 cells in response to EGF, but no change for IMC-3 and IMC-4 cells. We examined response to EGF of IMC-2 cells with regard to expression of a growth-related oncogene (c-fos), proteinases and their inhibitors. Expression of c-fos was transiently increased in IMC-2 cells at rates comparable to those seen in the 2 other lines in the presence of EGF. There was no apparent effect of EGF on the expression of urokinase-type plasminogen activator and 72-kDa type-IV collagenase in IMC-2 cells. In contrast, EGF specifically enhanced the expression of plasminogen activator inhibitor-I (PAI-I) and tissue inhibitor of metalloproteinases-I (TIMP-I) in IMC-2 cells. Our data suggest that proteinase inhibitors or other related factors may play an important role in tumor growth and invasion in response to EGF.
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PMID:The response to epidermal growth factor of human maxillary tumor cells in terms of tumor growth, invasion and expression of proteinase inhibitors. 165 98

The fosB gene encodes a nuclear protein that shows a high degree of homology with c-Fos in several of the known functionally crucial domains, e.g., the leucine zipper and the DNA-binding site, but shows considerable divergence in other regions. Here, we report that FosB, when placed under the control of a constitutive promoter, exhibits clear transforming properties in focus assays using mouse NIH3T3 or rat 208F fibroblasts. The transforming potential of FosB is considerably stronger than that of a corresponding c-fos construct and resembles that of viral fos genes. Using chimeric fos/fosB constructs we show that the C-terminal half of FosB is responsible for these stronger transforming properties, apparently by giving rise to significantly higher levels of protein as compared with the corresponding c-fos sequence. Surprisingly, substitution of the N-terminus of Fos with that of FosB decreases its transforming potential. These differences in the transforming potential are not related to DNA or protein expression, but rather seem to reflect differences in the molecular function(s) encoded in the N-terminal halves of Fos and FosB protein. Both, fosB- and v-fos transformed cells show increased expression of a number of endogenous genes, including c-jun, transin, alpha 1(III) collagen and tissue plasminogen activator. Transactivation by FosB and v-fos of the c-jun and alpha 1(III) collagen gene promoters and of a 3 x TRE-tk chimeric promoter could be shown in transient CAT assays. v-Fos, but not FosB-transformed cells, also show elevated levels of urokinase and plasminogen activator inhibitor mRNAs, pointing to potential differences in the gene regulatory properties of the two Fos family members.
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PMID:fosB is a transforming gene encoding a transcriptional activator. 190 95

Phorbol esters, by activating protein kinase C (PKC), induce the expression of the urokinase-type plasminogen activator (uPA) gene and the proto-oncogene c-fos in LLC-PK1 (PK1) porcine kidney epithelial cells. To investigate the role of PKC in the regulation of these two 12-O-tetradecanoylphorbol-13-acetate (TPA)-inducible genes, the alpha-type PKC, the predominant subtype present in the PK1 cells, was overexpressed in this cell line. Two clonal PK1 derivatives overexpressing the alpha PKC 15- and 20-fold, respectively, were established. Compared with the parental and control cells, only a modest but substantially sustained (2- to 3-fold) increase in the accumulation of uPA as well as c-fos mRNAs were observed by TPA in these cells. These results indicate that the extent of induction of these genes mediated by TPA was not proportional to the amounts of alpha-type PKC stably overexpressed in these cells, suggesting that factor(s) downstream of the activation of the alpha PKC appear to be rate limiting for the induction of both TPA-inducible genes in PK1 cells.
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PMID:Overexpression of the alpha-type protein kinase (PK) C in LLC-PK1 cells does not lead to a proportional increase in the induction of two 12-O-tetradecanoylphorbol-13-acetate-inducible genes. 190 83

A single topical treatment of mouse skin with the potent tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) results in transient inductions of a variety of genes. Based on the time courses of their inductions, these genes can be classified into two main groups: "early" response genes whose mRNA expression reaches a maximum 0.5-2 h after TPA treatment and "secondary" response genes whose mRNA expression is maximal 4 h or more after treatment. The nuclear oncogenes c-fos, c-myc, and c-jun belong to the early response group, whereas the metallothionein, osteopontin, and urokinase genes belong to the secondary response group. The steady-state expressions of these early and secondary response genes are all very low in normal skin, except that of c-jun, which is relatively high. Steady-state levels of expression and inducibility of these genes by TPA were not altered in initiated skin or in apparently normal skin during tumor promotion. We examined the expressions of these genes in papillomas and carcinomas produced by two-stage (initiator-promoter) and three-stage (initiator-promoter-initiator) protocols in mouse skin. Steady-state expression of the early responding nuclear oncogenes in papillomas and carcinomas was found to remain at the same low level as in normal skin. However, all the secondary responding genes were found to be expressed constitutively at high levels in these tumors. Elevated expressions of the genes for transforming growth factor alpha and beta were also observed in papillomas and to varying extents in carcinomas. These observations suggest that the regulatory machinery for transcription by the protein kinase C-mediated pathway through nuclear oncogenes is altered during the processes of tumor promotion and progression. The genes whose expression is elevated may be associated directly or indirectly with tumor promotion and progression.
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PMID:Elevated expression of secondary, but not early, responding genes to phorbol ester tumor promoters in papillomas and carcinomas of mouse skin. 212 8

Human SH-SY5Y neuroblastoma cells treated with retinoic acid, 12-O-tetradecanoyl-phorbol-13-acetate (TPA) or nerve growth factor differentiated morphologically to neuronlike cells with increased amounts of neurofilament protein and mRNA. All three effectors induced an increase in the amount of relative molecular weight (Mr) 70,000 tissue-type plasminogen activator (t-PA) and its mRNA, as determined by immunocapture, enzyme activity, and Northern blotting analyses. About 90% of the t-PA activity was secreted to the culture medium. In contrast, of the three effectors studied, only TPA induced transcription of the proto-oncogene c-fos, studied as a control gene responsive to various stimuli, and induced a rapid increase in urokinase-type PA (u-PA). Most of the u-PA activity induced by TPA remained cell-associated. Because induction of differentiation correlated closely with induction of t-PA, and not u-PA, the authors propose that t-PA may have a functional role in the morphological differentiation of neuronal cells.
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PMID:Induction of morphological differentiation of human neuroblastoma cells is accompanied by induction of tissue-type plasminogen activator. 250 35

Marked changes in c-fos proto-oncogene mRNA level and transcription rate were observed upon modulation of the functional activity of cultured mouse peritoneal macrophages. Cholera toxin (CT), dexamethasone (dex), interferon-gamma (IFN-gamma), concanavalin A (Con A), and endotoxin (LPS) induced changes in mRNA levels and transcription rates of both urokinase-type plasminogen activator and tumor necrosis factor/cachectin genes, the products of which are sensitive indices of macrophage activity. All of these agents also caused rapid and transient changes in c-fos gene expression, either enhancement (CT, dex, and LPS) or decrease (IFN-gamma and Con A). Moreover, inhibition of protein synthesis elicited a transient increase in the level of c-fos gene transcription, suggesting that the transcriptional activity of the c-fos gene is controlled by labile protein repressor(s). Taken together, these results suggest a possible role for the c-fos gene product, a nuclear protein, in the modulation of the functional activity of differentiated macrophages.
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PMID:Modulations of functional activity in differentiated macrophages are accompanied by early and transient increase or decrease in c-fos gene transcription. 311 Feb 91

The effect of RU 486, a synthetic steroid that is a powerful antagonist of glucocorticoid hormones, was tested on the transcription of several glucocorticoid-regulated genes in different cell types: inflammatory murine macrophages and two human mammary gland-derived cell lines, MDA-MB-231 and HBL-100. The transcription of genes which are positively regulated by glucocorticoids (e.g., tissue-type plasminogen activator and c-myc in mammary cells, c-fos in macrophages) and that of genes which are negatively regulated by these agents (e.g., urokinase-type plasminogen activator in all three cell types, TNF-a and IL-1 in macrophages) was explored. RU 486 almost completely prevented the effects of dexamethasone on the transcription of these various genes. When added alone, RU 486 had essentially no agonist activity.
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PMID:Antagonist effect of RU 486 on transcription of glucocorticoid-regulated genes. 312 70

In this study, the sequences of several cellular genes (c-myc, c-fos, c-sis, c-mos, and the genes for urokinase, heat shock proteins, interleukin-2 and its receptor), thought to be controlled by negative regulatory factors, were examined. As a result of this comparison, multiple (and often clustered) copies of a 12 basepair (bp) element were identified in the flanking regions of these genes. Moreover, sequences with close homology to this 12 bp element were identified in specific control regions of some DNA and RNA tumor viruses. A consensus sequence (TTG nnn TTTTTT) was derived from an analysis of 111 of these elements. These sequence homologies have yielded a coherent first hypothesis, namely that this 12 bp element is the binding site of a transcriptional repressor protein.
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PMID:Putative repressor binding sites in the regions mediating transcriptional control of viral and cellular genes. 408 73


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