Human urokinase receptor expression is inhibited by amiloride and induced by tumor necrosis factor and phorbol ester in colon cancer cells

Wang, Yao; Jones, Chris; Dang, Jinjun; Liang, Xinghua; Olsen, Jane E.; Doe, William F.

doi:10.1016/0014-5793(94)01032-3

Cited by 42 publications

(29 citation statements)

References 33 publications

(31 reference statements)

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“…We and others showed that TGF-b and TNF-a increase expression of uPAR through transcriptional and posttranscriptional mechanisms (15,26,16,33). Because these cytokines have also been reported to regulate LRP-1 expression in other cell types (28,29,34), we sought to determine the role of TNF-a, TGF-b, and IL-1b on LRP-1 expression in PMCs.…”

Section: Discussionmentioning

confidence: 99%

Lipoprotein Receptor–Related Protein 1 Regulates Collagen 1 Expression, Proteolysis, and Migration in Human Pleural Mesothelial Cells

Tucker

Williams

Koenig

et al. 2012

Am J Respir Cell Mol Biol

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The low-density lipoprotein receptor-related protein 1 (LRP-1) binds and can internalize a diverse group of ligands, including members of the fibrinolytic pathway, urokinase plasminogen activator (uPA), and its receptor, uPAR. In this study, we characterized the role of LRP-1 in uPAR processing, collagen synthesis, proteolysis, and migration in pleural mesothelial cells (PMCs). When PMCs were treated with the proinflammatory cytokines TNF-a and IL-1b, LRP-1 significantly decreased at the mRNA and protein levels (70 and 90%, respectively; P , 0.05). Consequently, uPA-mediated uPAR internalization was reduced by 80% in the presence of TNF-a or IL-1b (P , 0.05). In parallel studies, LRP-1 neutralization with receptor-associated protein (RAP) significantly reduced uPA-dependent uPAR internalization and increased uPAR stability in PMCs. LRP-1-deficient cells demonstrated increased uPAR t 1/2 versus LRP-1-expressing PMCs. uPA enzymatic activity was also increased in LRP-1-deficient and neutralized cells, and RAP potentiated uPA-dependent migration in PMCs. Collagen expression in PMCs was also induced by uPA, and the effect was potentiated in RAP-treated cells. These studies indicate that TNF-a and IL-1b regulate LRP-1 in PMCs and that LRP-1 thereby contributes to a range of pathophysiologically relevant responses of these cells.Keywords: pleural mesothelial cells; uPAR; LRP-1; internalization; half-lifeThe low-density lipoprotein receptor-related protein 1 (LRP-1) is a 600-kD surface receptor composed of a 515-kD a-ligand binding domain that is noncovalently associated with an 85-kD b-transmembrane domain (1, 2). LRP-1 is a member of the low-density lipoprotein receptor (LDLR) family, which includes the very low-density lipoprotein receptor and gp330/megalin. Members of the LDLR family share structural homology. They also play an important role in the internalization of diverse surface receptors and ligands, including a-2 macroglobulin, Pseudomonas exotoxin, urokinase plasminogen activator (uPA), plasminogen activator inhibitor (PAI)-1, and the uPA cognate receptor (uPAR) (3-5). Members of the LDLR family bind ligands with different affinities. The ability of LRP-1 in particular to bind such a diverse group of ligands suggests that it could play an important role in tissue remodeling, protein metabolism, and proteolytic activity. The receptor-associated protein (RAP) is a cytosolic chaperone for LRP-1; however, it also blocks the binding of natural ligands for members of the LDLR family, thus neutralizing their endocytotic function (6-8). We found that LRP-1 is expressed by PMCs in normalcy and disease, leading us to infer that it might influence a range of pathophysiologically relevant responses of these cells.LRP-1 regulates cell motility (9) that involves members of the fibrinolytic pathway, specifically uPA and uPAR (9-11). LRP-1 has also been shown to regulate cellular fibrinolytic activity by rapidly internalizing single-chain uPA and the uPA/PAI-1/uPAR complex (12-14). Further, a motif on D3 of uPAR is believed...

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Section: Discussionmentioning

confidence: 99%

Lipoprotein Receptor–Related Protein 1 Regulates Collagen 1 Expression, Proteolysis, and Migration in Human Pleural Mesothelial Cells

Tucker

Williams

Koenig

et al. 2012

Am J Respir Cell Mol Biol

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“…It has previously been reported that expression of uPA and uPAR, as well as their specific interaction, is enhanced by proinflammatory agents, such as LPS, TGF-b, and TNF-a in various cell lines (12,(32)(33)(34)(38)(39)(40)(41). These agents intensely and rapidly induce cell surface uPAR expression and the effect that can be traced back to a rapid, antecedent increase in the cellular level of uPAR mRNA.…”

Section: Discussionmentioning

confidence: 99%

“…The uPAR focuses uPA-dependent pericellular proteolysis. In addition, interaction of uPA and uPAR facilitates cellular proteolysis, cell proliferation, adhesion, and migration in diverse cell types of many organs, including lung, during infection or injury (12,32,(37)(38)(39)(40)(41).…”

Section: Discussionmentioning

confidence: 99%

Post-Transcriptional Regulation of Urokinase-type Plasminogen Activator Receptor Expression in Lipopolysaccharide-induced Acute Lung Injury

Bhandary¹,

Velusamy²,

Shetty³

et al. 2009

Am J Respir Crit Care Med

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Rationale: Urokinase-type plasminogen activator (uPA) receptor (uPAR) is required for the recruitment of neutrophils in response to infection. uPA induces its own expression in lung epithelial cells, which involves its interaction with cell surface uPAR. Regulation of uPAR expression is therefore crucial for uPA-mediated signaling in infectious acute lung injury (ALI). Objectives: To determine the role of uPA in uPAR expression during ALI caused by sepsis. Methods: We used Western blot, Northern blot, Northwestern assay, and immunohistochemistry. Phosphate-buffered saline-and lipopolysaccharide (LPS)-treated wild-type and uPA 2/2 mice were used. Measurements and Main Results: Biological activities of uPA, including proteolysis, cell adhesion, migration, proliferation, and differentiation, are dependent on its association with uPAR. Bacterial endotoxin (LPS) is a major cause of pulmonary dysfunction and infectionassociated mortality. The present study shows that LPS induces uPAR expression both in vitro and in vivo, and that the mechanism involves post-transcriptional stabilization of uPAR mRNA by reciprocal interaction of phosphoglycerate kinase (PGK) and heterogeneous nuclear ribonucleoprotein C (hnRNPC) with uPAR mRNA coding region and 39 untranslated region determinants, respectively. The process involves tyrosine phosphorylation of PGK and hnRNPC. uPA 2/2 mice failed to induce uPAR expression after LPS treatment. In these mice, LPS treatment failed to alter the binding of PGK and hnRNPC protein with uPAR mRNA due to lack of tyrosine phosphorylation. Conclusions: Our study shows that induction of LPS-mediated uPAR expression is mediated through tyrosine phosphorylation of PGK and hnRNPC. This involves expression of uPA as an obligate intermediary.

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“…Lipopolysaccharide (LPS), the toxic moiety of the gram-negative bacterial cell membrane, can enhance uPAR expression on monocytes (5). Although tumor necrosis factor alpha (TNF) is capable of increasing uPAR mRNA levels in monocytic cells and colon cancer cell lines (21,35), reports on the ability of this proinflammatory cytokine to induce uPAR expression on the surface of monocytic cells are conflicting (31,35). After LPS administration to mice, increased uPAR mRNA levels were detected in most tissues examined (4).…”

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confidence: 99%

Upregulation of Monocyte Urokinase Plasminogen Activator Receptor during Human Endotoxemia

et al. 2000

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The receptor for urokinase-type plasminogen activator (uPAR) (CD87) plays an important role in leukocyte adhesion and migration. To assess the effect of endotoxin on cellular uPAR, uPAR expression was determined on leukocytes by fluorescence-activated cell sorter analysis in seven healthy subjects following intravenous injection of endotoxin (lot G; 4 ng/kg). Endotoxin induced a transient increase in uPAR expression on monocytes, reaching a 92% ؎ 46% increase over baseline expression after 6 h (P < 0.05). Endotoxin did not influence uPAR expression on granulocytes, while uPAR remained undetectable on lymphocytes. Endotoxin also increased soluble uPAR levels in plasma (P < 0.05). Stimulation of human whole blood with endotoxin or gram-positive stimuli in vitro also resulted in an upregulation of monocyte uPAR expression. Although tumor necrosis factor alpha (TNF) upregulated monocyte uPAR expression, anti-TNF did not influence the endotoxin-induced increase in monocyte uPAR expression. These data suggest that infectious stimuli may influence monocyte function in vivo by enhancing the expression of uPAR.

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Human urokinase receptor expression is inhibited by amiloride and induced by tumor necrosis factor and phorbol ester in colon cancer cells

Cited by 42 publications

References 33 publications

Lipoprotein Receptor–Related Protein 1 Regulates Collagen 1 Expression, Proteolysis, and Migration in Human Pleural Mesothelial Cells

Lipoprotein Receptor–Related Protein 1 Regulates Collagen 1 Expression, Proteolysis, and Migration in Human Pleural Mesothelial Cells

Post-Transcriptional Regulation of Urokinase-type Plasminogen Activator Receptor Expression in Lipopolysaccharide-induced Acute Lung Injury

Upregulation of Monocyte Urokinase Plasminogen Activator Receptor during Human Endotoxemia

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