Urokinase-type plasminogen activator: proenzyme, receptor, and inhibitors

Blasi, Francesco; Vassalli, Jean‐Dominique; Danø, Keld

doi:10.1083/jcb.104.4.801

Cited by 585 publications

(296 citation statements)

References 69 publications

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“…The uPA cDNA probe consisted of a 1.5-kb Pstl insert cloned from human SV40-transformed fibroblast (Blasi et al, 1987), and the uPAR cDNA probe consisted of a 1.11-kb EcoRI/Xbal insert cloned from the human fibroblast GM637 cell line which was SV40-transformed (Roldan et al, 1990). Both cDNAs were obtained from the American Type Culture Collection (ATCC, Rockville, MD, USA).…”

Section: Northern Blot Analysismentioning

confidence: 99%

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Enhanced expression of urokinase plasminogen activator and its receptor in pancreatic carcinoma

Cantero

Frieß²,

Deflorin³

et al. 1997

Br J Cancer

186

126

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Summary Urokinase plasminogen activator (uPA) is a serine proteinase that has been suggested to play an important role in cancer invasion and metastasis. It binds to a specific membrane receptor denominated uPA receptor (uPAR Pancreatic cancer has one of the poorest prognoses of all gastrointestinal malignancies, being the fourth or fifth leading cause of cancer-related deaths in Western industrialized countries (Bomman et al, 1994). Gudjonsson (1987), in his classical review of 37 000 patients with pancreatic cancer, demonstrated an overall survival rate of 0.4% and a median survival time of 5 months after the diagnosis was established. Once pancreatic cancer is clinically evident, it progresses at a rapid rate, and metastasis has usually occurred at the time of diagnosis. Consequently, many patients are not resectable at presentation, and the overall resection rate is often less than 30% (Gudjonsson 1987;Bomman et al, 1994). The mechanisms that regulate this aggressive growth behaviour in pancreatic cancer are not at all clear. Recently, it has been shown in pancreatic cancer that the concomitant overexpression of the epidermal growth factor (EGF) receptor and its ligands EGF-, TGF-alpha (Korc et al, 1992;Yamanaka et al, 1993a) and/or amphiregulin (Ebert et al, 1994a; Yokoyama et al., 1995a) is associated with shorter post-operative survival following tumour resection. In addition, enhanced expression of c-erbB-3 (Friess et al, 1995), TGF-fs and basic fibroblast growth

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Section: Northern Blot Analysismentioning

confidence: 99%

“…It is tPA rather than uPA that is mainly involved in physiological activation of plasmin during intravascular thrombolysis (Collen, 1985). On the other hand, uPA appears to play a pivotal role in pericellular proteolysis during cell migration and tissue remodelling (Blasi et al, 1987).…”

mentioning

confidence: 99%

Enhanced expression of urokinase plasminogen activator and its receptor in pancreatic carcinoma

Cantero

Frieß²,

Deflorin³

et al. 1997

Br J Cancer

186

126

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“…PAI-1 is an important regulator of plasminogen activation and thus of extracellular proteolytic events, including fibrinolysis and degradation of the extracellular matrix (1,6). The induction of PAI-1 protein by * Corresponding author.…”

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confidence: 99%

Transforming growth factor beta 1-responsive element: closely associated binding sites for USF and CCAAT-binding transcription factor-nuclear factor I in the type 1 plasminogen activator inhibitor gene.

Riccio¹,

Pedone²,

Lund³

et al. 1992

Mol. Cell. Biol.

103

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Transforming growth factor 13 (TGF-3) is the name of a group of closely related polypeptides characterized by a multiplicity of effects, including regulation of extracellular proteolysis and turnover of the extracellular matrix. Its cellular mechanism of action is largely unknown. TGF-131 is a strong and fast inducer of type 1 plasminogen activator inhibitor gene transcription. We have identified a TGF-131-responsive element in the 5'-flanking region of the human type 1 plasminogen activator inhibitor gene and shown that it is functional both in its natural context and when fused to a heterologous nonresponsive promoter. Footprinting and gel retardation experiments showed that two different nuclear factors, present in extracts from both TGF-131-treated and nontreated cells, bind to adjacent sequences contained in the responsive unit. A palindromic sequence binds a trans-acting factor(s) of the CCAAT-binding transcription factor-nuclear factor I family. A partially overlapping dyad symmetry interacts with a second protein that much evidence indicates to be USF. USF is a transactivator belonging to the basic helix-loop-helix family of transcription factors. Mutations which abolish the binding of either CCAAT-binding transcription factor-nuclear factor I or USF result in reduction of transcriptional activation upon exposure to TGF-131, thus showing that both elements of the unit are necessary for the TGF-131 response. We discuss the possible relationship of these findings to the complexity of the TGF-13 action.Transforming growth factor I0 (TGF-3) is a general regulator of cellular activities with a multiplicity of effects in the normal organism. TGF-ps include a group of chemically closely related 25,000-Mr dimeric polypeptides, TGF-pl, , with largely identical effects. (Unless otherwise specified, "TGF-P3" will refer to TGF-fi1 heterodimers throughout the rest of the text.) TGF-,B can be synthesized by most cells of the organism and is stored in large quantities in blood platelets. It acts presumably in an autocrine and paracrine manner. Besides affecting cellular proliferation, TGF-3 influences the differentiation of several cell types; for instance, it inhibits myogenesis and adipogenesis and stimulates chondrogenesis. TGF-, regulates the turnover of the extracellular matrix. It stimulates production by fibroblasts of extracellular matrix components, such as type I, II, and III procollagen, fibronectin, and proteoglycans, and of cellular receptors for such proteins. TGF-1 inhibits production of enzymes catalyzing degradation of the extracellular matrix and stimulates production of inhibitors of such enzymes (22,27,31,41,47).It has previously been demonstrated that TGF-p induces type 1 inhibitor of plasminogen activators (PAI-1) in cultured human fibroblasts (24,26). PAI-1 is an important regulator of plasminogen activation and thus of extracellular proteolytic events, including fibrinolysis and degradation of the extracellular matrix (1, 6). The induction of PAI-1 protein by * Corresponding author. TGF-0 was la...

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“…Its expression by a variety of migratory cells (reviewed in references 2-4) and more particularly its polarization at the leading edge of migrating cells (5,6) has suggested involvement in cell invasion through extracellular matrices. Localized extracellular proteolysis may play a role in physiological processes such as macrophage invasion, ovulation, angiogenesis, wound healing, and in pathological conditions including inflammation and cancer metastasis (2)(3)(4)7). The u-PAR was shown to be a highly glycosylated 55-60-kD cell surface protein linked to the cell membrane by a glycosylphosphatidylinositol anchor (8,9).…”

Section: Introductionmentioning

confidence: 99%