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)

Invasion of tissue by macrophages and implantation into the uterine wall by placental trophoblasts are known to be regulated by the macrophage colony-stimulating factor (CSF-1) and its receptor (CSF-1R, the product of the c-fms proto-oncogene). Recently, the clinical importance of CSF-1 and CSF-1R in invasive breast carcinoma has been recognized, but the significance of coexpression of CSF-1 and CSF-1R in mammary epithelial cell invasion has not been explored. In the present study, we investigated the invasive potential of a noninvasive, CSF-1R-negative, mouse mammary epithelial cell line (HC11) expressing a high level of CSF-1, which was stably transfected with the mouse wild-type CSF-1R. Compared with parental cells, transfected cells expressing a wild-type CSF-1R invaded 100-fold more efficiently through a barrier of reconstituted basement membrane (Matrigel) and formed colonies in soft agar, whereas the cellular growth rate was only slightly increased. Analysis of cell-conditioned medium by zymography and quantitative enzyme activity assays showed that clones transfected with a wild-type CSF-1R expressed significantly higher levels of urokinase-type plasminogen activator than did untransfected clones. Furthermore, after injection into the tail veins of BALB/c mice, CSF-1R-expressing clones also produced a 10-fold higher incidence of lung tumors than the parental cell line. We also analyzed HC11 clones transfected with CSF-1R mutated at two major autophosphorylation sites (Tyr-->Phe807 and Tyr-->Phe721). Mutation at Tyr807 eradicated the stimulatory effect of Fms expression on the invasive ability of HC11 cells and substantially reduced the metastatic potential of the transfected clones but did not alter the Fms-induced anchorage-independent growth in soft agar. In contrast, mutation at Tyr721 of Fms had no effect on invasion as measured in the in vitro assay but markedly abolished Fms-induced colony formation in soft agar and eradicated the metastatic potential of the transfected clones. Our results suggest that expression of CSF-1R can facilitate cellular invasion and anchorage-independent growth in mammary epithelial cells, and these two processes are independently regulated by separate phosphotyrosine sites of CSF-1R.
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PMID:Independent regulation of invasion and anchorage-independent growth by different autophosphorylation sites of the macrophage colony-stimulating factor 1 receptor. 897 Nov 79

Cells of the mononuclear phagocyte lineage possess receptors for macrophage colony-stimulating factor (CSF-1) encoded by the c-fms protooncogene and respond to CSF-1 with increased survival, growth, differentiation, and reversible changes in function. The c-fms gene is itself a macrophage differentiation marker. In whole mount analyses of mRNA expression in embryos, c-fms is expressed at very high levels on placental trophoblasts. It is detectable on individual cells in the yolk sac around 8.5 to 9 days postcoitus, appears on isolated cells in the head of the embryo around 9.5 dpc, and appears on numerous cells throughout the embryo by day 10.5. The extent of c-fms expression is much greater than for other macrophage-specific genes including lysozyme and a macrophage-specific protein tyrosine phosphatase. Our studies of the cis-acting elements of the c-fms promoter have indicated a key role for collaboration between the macrophage-specific transcription factor, Pu.1, which functions in determining the site of transcription initiation, and other members of the Ets transcription factor family. This is emerging as a common pattern in macrophage-specific promoters. We have shown that two PU box elements alone can function as a macrophage-specific promoter. The activity of both the artificial promoter and the c-fms promoter is activated synergistically by coexpression of Pu.1 and another Ets factor, c-Ets-2. A 3.5kb c-fms exon 2 promoter (but not the 300bp proximal promoter) is also active in a wide diversity of tumor cell lines. The interesting exception is the melanoma cell line K1735, in which the promoter is completely shut down and expression of c-fms causes growth arrest and cell death. The activity of the exon 2 promoter in these nonmacrophages is at least as serum responsive as the classic serum-responsive promoter of the c-fos gene. It is further inducible in nonmacrophages by coexpression of the c-fms product. Unlike other CSF-1/c-fms-responsive promoters, the c-fms promoter is not responsive to activated Ras even when c-Ets-2 is coexpressed. In most lines, production of full length c-fms is prevented by a downstream intronic terminator, but in Lewis lung carcinoma, read-through does occur, and expression of both c-fms and other macrophage-specific genes such as lysozyme and urokinase becomes detectable in conditions of serum deprivation.
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PMID:Regulation of CSF-1 receptor expression. 898 63

The expression and function of CSF-1 and its receptor were studied in tumors of the human breast, ovary, and endometrium. CSF-1 and its receptor, initially implicated as essential to normal monocyte development and trophoblastic implantation, have been more recently shown to be expressed by carcinomas of the breast and other epithelia of the female reproductive tract where activation of the receptor by ligand produced either by the tumor cells or by stromal elements stimulates tumor cell invasion by a urokinase-dependent mechanism. Breast carcinomas express wild-type CSF-1 receptors (CSF-1R) at levels comparable to those observed in trophoblast and monocytes. Ovarian and endometrial carcinomas express significantly lower levels of wild-type, functional CSF-1Rs, while ovarian carcinomas also express unusual transcripts that diverge from the wild-type CSF-1R transcript in their 5' extracellular domain sequences. Tumor cell expression of CSF-1R is under the control of several steroid hormones (glucocorticoids and progestins) and the binding of several bHLH transcription factors, while tumor cell expression of CSF-1 appears to be regulated by other hormones, some of which are involved in normal lactogenic differentiation. In addition, tumor cells often produce CSF-1 at such high levels that the cytokine spills into the extracellular fluid and circulation. Measurements of circulating levels of CSF-1 have proved useful in patients with ovarian, endometrial, and breast carcinoma both for disease detection and monitoring of response to therapy. CSF-1 and its receptor appear to be an important receptor/ligand pair in the biology of breast cancers and tumors of the female reproductive tract where they may regulate functions similar to those they control during macrophage activation and placental implantation.
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PMID:CSF-1 and its receptor in breast carcinomas and neoplasms of the female reproductive tract. 898 66

An antibody that specifically recognized phosphothreonine 72 in ets-2 was used to determine the phosphorylation status of endogenous ets-2 in response to colony-stimulating factor 1 (CSF-1)/c-fms signaling. Phosphorylation of ets-2 was detected in primary macrophages, cells that normally express c-fms, and in fibroblasts engineered to express human c-fms. In the former cells, ets-2 was a CSF-1 immediate-early response gene, and phosphorylated ets-2 was detected after 2 to 4 h, coincident with expression of ets-2 protein. In fibroblasts, ets-2 was constitutively expressed and rapidly became phosphorylated in response to CSF-1. In both cell systems, ets-2 phosphorylation was persistent, with maximal phosphorylation detected 8 to 24 h after CSF-1 stimulation, and was correlated with activation of the CSF-1 target urokinase plasminogen activator (uPA) gene. Kinase assays that used recombinant ets-2 protein as a substrate demonstrated that mitogen-activated protein (MAP) kinases p42 and p44 were constitutively activated in both cell types in response to CSF-1. Immune depletion experiments and the use of the MAP kinase kinase inhibitor PD98059 indicate that these two MAP kinases are the major ets-2 kinases activated in response to CSF-1/c-fms signaling. In the macrophage cell line RAW264, conditional expression of raf kinase induced ets-2 expression and phosphorylation, as well as uPA mRNA expression. Transient assays mapped ets/AP-1 response elements as critical for basal and CSF-1-stimulated uPA reporter gene activity. These results indicate that persistent activation of the raf/MAP kinase pathway by CSF-1 is necessary for both ets-2 expression and posttranslational activation in macrophages.
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PMID:Persistent activation of mitogen-activated protein kinases p42 and p44 and ets-2 phosphorylation in response to colony-stimulating factor 1/c-fms signaling. 971 May 99

High levels of plasminogen activator inhibitor-1 (PAI-1) in tissue extracts have been associated with poor prognosis in many epithelial cancers. Ovarian cancers contain a higher concentration of PAI-1 than benign ovarian tumors or normal ovaries. Reports, however, on the prognostic value of PAI-1 content in ovarian cancers have been conflicting. We used immunohistochemistry to study the primary and metastatic tissues from 131 epithelial ovarian cancer cases. This group has been previously characterized for the expression of urokinase (uPA), uPA receptor, PAI-2 and macrophage colony-stimulating factor (CSF-1). The intensity and extent of staining for PAI-1 in the tumor epithelium was scored. Kaplan-Meier curves of survival were compared using the log-rank test. The Cox regression model was utilized for multivariate analysis. Approximately 50% of the primary tumors and metastases expressed PAI-1. Among invasive stages III and IV patients, those whose primary tumors expressed PAI-1 had a shorter overall survival. The combination of strong expression of PAI-1 and expression of uPA was a highly significant factor for short disease-free and overall survival. Similar results were seen with the combination of high PAI-1 and low PAI-2 expression. Strong PAI-1 expression was significantly associated with expression of uPA receptor or CSF-I in the tumor epithelium, but not with standard clinical parameters, and was an independent prognostic factor for poor survival on multivariate analysis. Our results show that PAI-1 expression in the primary tumor epithelium is an independent poor prognostic factor for survival, underscoring the tumor protective role of PAI-1 in ovarian cancer biology.
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PMID:Plasminogen activator inhibitor-1 is an independent poor prognostic factor for survival in advanced stage epithelial ovarian cancer patients. 976 Nov 11

Human ovarian adenocarcinoma cells N.1 secrete an autocrine activity that stimulates active cell death under serum-reduced conditions. To substitute the autocrine activity by a single physiological component, 28 cytokines, growth factors and biomodulators were tested [interleukin 1alpha (IL-1alpha), IL-1beta, IL-2, IL-3, IL-4, IL-6, IL-10, IL-11, stem cell factor (SCF), platelet-derived growth factor (PDGF), acid fibroblast growth factor (aFGF), basic fibroblast growth factor (bFGF), insulin-like growth factor (IGF-1), IGF-2, insulin, macrophage colony-stimulating factor (M-CSF), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), oncostatin, RANTES (regulated on activation normal T cell expressed and secreted), angiogenin, leukaemia inhibitory factor (LIF), erythropoietin (EPO), interferon alpha (INF-alpha), INF-gamma, transferrin, tumour necrosis factor alpha (TNF-alpha, TNF-beta and bovine serum albumin for control reasons]. In these experiments, only TNF-alpha and TNF-beta rapidly induced apoptosis. TNF-alpha and TNF-receptor 1 were expressed by N.1 cells, and the secretion of TNF-alpha was verified by enzyme-linked immunosorbent assay (ELISA). Autocrine factor-triggered apoptosis was inhibited when conditioned supernatant was preincubated with anti-TNF-alpha antibody. These findings suggested that the apoptosis-inducing component of the N.1 autocrine activity was TNF-alpha. In the presence of antisense c-myc oligonucleotides, induction of cell death by autocrine factor was partly inhibited. Autocrine factor and TNF-alpha stimulated transcription of the invasiveness-related protease plasminogen activator/urokinase mRNA (upa) with similar kinetics. When N.1 cells were exposed to purified plasminogen activator/urokinase protein (uPA), cell matrix contact was disrupted. Thus, uPA might serve a physiological role during TNF-induced apoptosis by affecting the interactions between cells and the basal membrane, thereby facilitating anoikis. This mechanistic study, which was restricted to a single human ovarian carcinoma model cell line (N.1), provides evidence that N.1 maintains the capacity to undergo c-myc-dependent apoptosis by the TNF-TNF-receptor pathway, and no additional pharmacological stimuli for induction of apoptosis are required.
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PMID:Autocrine self-elimination of cultured ovarian cancer cells by tumour necrosis factor alpha (TNF-alpha). 976 76

Colony stimulating factor (CSF-1) and its receptor (CSF-1R, product of c-fms proto-oncogene) were initially implicated as essential for normal monocyte development as well as for trophoblastic implantation. However, recent findings have suggested that CSF-1 and CSF-1R might have additional roles in mammary gland development during pregnancy and lactation. Studies with osteopetrotic (op-/op-) mice, which bear a specific mutation that inactivates the CSF-1 gene, demonstrated that op-/op- mothers are incapable of normal milk production due to the incomplete development of their mammary glands during pregnancy. Also, significant increases in the levels of CSF-1 and CSF-1R proteins are observed in the epithelial cells of mammary gland during pregnancy and lactation. In vitro studies investigating the effect of the three major lactogenic hormones (prolactin, insulin, and glucocorticoids) on the expression of CSF-1 and CSF-1R have demonstrated that expression of CSF-1 can be regulated by prolactin and insulin whereas CSF-1R expression is regulated by glucocorticoids. This apparent role for CSF-1/CSF-1R in normal mammary gland development is very intriguing because this receptor/ligand pair has also been found to be important in the biology of breast cancer, where they regulate tumor cell invasion by a urokinase-dependent mechanism. This review aims to summarize recent findings on the role of CSF-1 and its receptor in normal and neoplastic mammary development which may elucidate potential relationships of growth factor-induced biological changes in the breast during pregnancy and tumor progression.
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PMID:The role of CSF-1 in normal and neoplastic breast physiology. 989 62

We and other researchers have previously found that colony-stimulating factors (CSFs), which generally include granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF), promote invasion by lung cancer cells. In the present study, we studied the effects of these CSFs on gelatinase production, urokinase plasminogen activator (uPA) production and their activity in human lung cancer cells. Gelatin zymographs of conditioned media derived from human lung adenocarcinoma cell lines revealed two major bands of gelatinase activity at 68 and 92 kDa, which were characterized as matrix metalloproteinase (MMP)-2 and MMP-9 respectively. Treatment with CSFs increased the 68- and 92-kDa activity and converted some of a 92-kDa proenzyme to an 82-kDa enzyme that was consistent with an active form of the MMP-9. Plasminogen activator zymographs of the conditioned media from the cancer cells showed that CSF treatment resulted in an increase in a 48-55 kDa plasminogen-dependent gelatinolytic activity that was characterized as human uPA. The conditioned medium from the cancer cells treated with CSFs stimulated the conversion of plasminogen to plasmin, providing a direct demonstration of the ability of enhanced uPA to increase plasmin-dependent proteolysis. The enhanced invasive behaviour of the cancer cells stimulated by CSFs was well correlated with the increase in MMPs and uPA activities. These data suggest that the enhanced production of extracellular matrix-degrading proteinases by the cancer cells in response to CSF treatment may represent a biochemical mechanism which promotes the invasive behaviour of the cancer cells.
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PMID:Granulocyte, granulocyte-macrophage, and macrophage colony-stimulating factors can stimulate the invasive capacity of human lung cancer cells. 1040 91

We investigate the regulation of plasminogen activator inhibitor-2 (PAI-2) in murine macrophages. PAI-2 mRNA was inducible by bacterial lipopolysaccharide (LPS) in primary cells and macrophage-like cell lines. Evidence is presented for a role for autocrine factors, including cyclooxygenase products but not the cytokines tumor necrosis factor alpha or interferon-beta (IFN-beta). PAI-2 mRNA levels generally varied inversely from those of its target, urokinase-type plasminogen activator (uPA), and the macrophage growth factor CSF-1, which induces uPA, inhibited PAI-2 expression in cells treated subsequently with LPS. Expression of PAI-2 was distinct from that of other LPS-inducible genes in terms of induction time course, LPS dose response, and sensitivity to co-stimulation with IFN-gamma. Induction of PAI-2 mRNA in subclones of the cell line RAW 264 was not uniform, reflecting heterogeneous expression in the parent line. The expression pattern of PAI-2 is discussed in terms of a possible role in LPS-induced pathology such as septicemia.
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PMID:Regulation of the plasminogen activator inhibitor-2 (PAI-2) gene in murine macrophages. Demonstration of a novel pattern of responsiveness to bacterial endotoxin. 1041 Oct 6

It has been shown that, in breast stroma, urokinase-type plasminogen activator (uPA) mRNA is predominantly expressed by myofibroblasts located at the invasive areas of the tumor. To examine which factors present in a tumor environment are candidates responsible for the induction of these uPA-producing myofibroblasts, we studied in vitro the capacity of a paired panel of normal and tumor-derived human breast fibroblasts to produce uPA protein and the myofibroblast marker alpha-smooth-muscle-actin (alpha-SMA) in response to various cytokines implicated in the process of tissue-remodeling during malignant transformation. We found that fibroblasts produced increased amounts of uPA protein after exposure to a-FGF, b-FGF, EGF, PDGF-BB, and IFN-gamma, were unaffected in this respect by IL-6, M-CSF, GM-CSF and Oncostatin M, and produced decreased amounts of uPA protein after exposure to IL-1alpha, TNF-alpha, IGF-I, and IGF-II. None of these cytokines were able to induce a striking increase in the fraction of alpha-SMA-positive fibroblasts. On the other hand, 25 pM TGFbeta1 increased the fraction of alpha-SMA-positive fibroblasts 5-fold in both normal and tumor-tissue-derived fibroblasts. Nonetheless, the normal-derived fibroblasts were unaffected in their uPA-producing capacity by TGFbeta1, and the tumor-derived fibroblasts produced decreased amounts of uPA protein after exposure to this cytokine, implying that at least in vitro the myofibroblast phenotype is not a prerequisite for the production of uPA by human breast fibroblasts. In addition, we established that the basal-uPA-production of both normal and tumor-derived fibroblasts was increased by autocrinely produced b-FGF-like activity, and that the basal-uPA-production of at least the normal-derived fibroblasts was decreased by autocrinely produced IGF-like activity. Altogether, our data suggest an active role for fibroblasts in the process of uPA-directed breast tumor proteolysis.
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PMID:Cytokine-regulated urokinase-type-plasminogen-activator (uPA) production by human breast fibroblasts in vitro. 1047 75


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