Proliferation of a human epidermal tumor cell line stimulated by urokinase

Kirchheimer, Johannes C.; Wojta, Johann; Christ, Guenter; Binder, Bernd R.

doi:10.1096/fasebj.1.2.3038646

Cited by 128 publications

(78 citation statements)

References 20 publications

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“…For certain epidermal cells, uPA has been found to be a weak mitogen, and the data have indicated that both the growth factor domain and the catalytic domain are necessary (42). In view ofthese observations, we measured the proliferative response of HL60 cells after stimulation with exogenous uPA (0.8-100 nM range), and found that there was no change in 3H-thymidine uptake or induction ofadherence.…”

Section: Methodsmentioning

confidence: 94%

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An autocrine role for urokinase in phorbol ester-mediated differentiation of myeloid cell lines.

Nusrat¹,

Chapman²

1991

J. Clin. Invest.

130

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The human myeloid cell line HL60 secretes urokinase-type plasminogen activator (uPA) and expresses its receptor. When stimulated with phorbol myristate acetate (PMA), both secretion of uPA and the expression of its receptor are up-regulated, and these cells differentiate to an adherent phenotype. This adhesive response is markedly reduced in the presence of uPA antibodies. The PMA response is restored by the addition of native uPA, an amino-terminal fragment of uPA (residues 1-143) devoid of proteolytic activity, or a synthetic peptide (residues 12-32) from the uPA growth factor domain known to mediate receptor binding. In contrast, the addition of catalytically active low molecular weight uPA, which is missing the growth factor domain, or a peptide from the catalytic domain (residues 247-266) is ineffective. The influence ofuPA antibodies on a second marker of macrophage differentiation, cysteine proteinase activity, was also examined. Cysteine proteinase activity of HL60 cells is increased in PMA-treated cells after 24 h but it fails to increase in the presence of anti-uPA. This increase in cathepsin B-like activity is also restored by exogenous uPA. These experiments indicate that an autocrine interaction of the growth factor domain of uPA with its receptor mediates an essential step in PMA-mediated myeloid cell differentiation. (J. Clin.

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Section: Methodsmentioning

confidence: 94%

“…It has been reported that for the CCL 20.2 human epidermal cell line that uPA can serve as an autocrine mitogen and stimulates thymidine incorporation (42 (7,27). An overnight adherence assay similar to that I described in Fig.…”

Section: Methodsmentioning

confidence: 99%

An autocrine role for urokinase in phorbol ester-mediated differentiation of myeloid cell lines.

Nusrat¹,

Chapman²

1991

J. Clin. Invest.

130

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“…These actions were caused by uPA binding to plasma membrane uPAR by its NH2-terminal region, which contains sequences that are homologous to the receptor-binding domain of EGF. The uPAgrowth factor domain is also responsible for the growth factorlike activity seen in human osteosarcoma and squamous carcinoma cells (60,61). By demonstrating that uPAR is also essential for chemotaxis, we extend the importance of uPAR beyond its established roles in anchoring uPA ectoenzyme activity and in signal transduction.…”

Section: Discussionmentioning

confidence: 99%

The urokinase receptor is required for human monocyte chemotaxis in vitro.

Gyetko¹,

Todd²,

Wilkinson³

et al. 1994

J. Clin. Invest.

298

218

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Mononuclear phagocytes (MO) produce urokinase-type plasminogen activator (uPA) and also express a specific cell-surface receptor for urokinase, uPAR. The concomitant expression of these proteins provides a mechanism by which MO can degrade extracellular matrix proteins during directed cell migration. In this study, we sought to determine if uPAR plays a role in MO chemotaxis that is distinct from its role in matrix proteolysis. Exposing adherent monocytes to a chemotactic gradient causes plasma membrane uPAR to localize strongly to the leading edge of cell migration. Adherence alone or exposure to FMLP had no effect on uPAR expression. Using Boyden chamber chemotaxis assays, we demonstrate that treating mononuclear cells with an anti-uPAR mAb (either as an intact mAb or Flab'12) ablates chemotaxis induced by FMLP and monocyte chemotactic peptide-1 (P < 0.001). Inactivating the catalytic activity of uPAR-bound uPA had no effect on chemotaxis. Similarly, blocking uPAR expression with an antisense oligonucleotide to uPAR completely ablates chemotaxis, but blocking uPA expression with an antisense oligonucleotide to uPA has a minimal effect. We therefore demonstrate that expression and unimpeded function of uPAR plays an obligate role in M6 chemotaxis by mechanisms that are largely independent of its ligand, uPA. Combined with its known role in mediating pericellular proteolysis, these observations demonstrate that uPAR is essential for both locomotion and traversing tissue barriers during MO migration. (J. Clin. Invest. 1994.

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“…Furthermore, interaction of uPA to uPAR is important for adhesion, motility and migration of cells (4). It was assumed that uPA can exert cytokine-like activity by increasing the proliferation of human epidermal tumor cells and malignant renal cells (5,6). uPA is subdivided into 3 domains: the N-terminal growth factor-like domain, the kringle domain and the C-terminal protease domain.…”

Section: Introductionmentioning

confidence: 99%

Urokinase-type plasminogen activator induces proliferation in breast cancer cells

Gandhari

Arens²,

Majety³

et al. 2006

Int J Oncol

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Abstract. Urokinase-type plasminogen activator (uPA) is implicated in various pathophysiological processes, including extracellular matrix turnover, cell migration and invasion. Our study aimed to determine the role of uPA in both proliferation and mitogen-activated protein kinase (MAPK) pathway. Hence, we analyzed the effects induced by exogeneous addition of domain-specific uPA antibodies and uPAinteracting molecules on proliferation of uPA-suppressed MDA-MB-231 breast cancer cells. uPA expression was reduced to 53% by stable transfection with an antisense/ vector construct and to 65% by siRNA transfection. Immunocytochemical Ki67 staining and flow cytometry (S-phase) analysis indicated a strong decrease of cellular proliferation activity (35% and 38%, respectively). Exogenous addition of high molecular weight-uPA (HMW-uPA) or incubation with the amino terminal fragment (ATF), which lacks the enzymatic activity of uPA, lead to increased cell proliferation. A strong increase of proliferation was absent when the monoclonal antiuPAR antibody IIIF10 (blocking uPA binding site), soluble uPAR (scavenger effect) and phosphatidyl-inositol-specific phopholipase C (PI-PLC, degrading uPAR) was added prior to the addition of HMW-uPA. In conclusion, HMW-uPA and ATF induce proliferation of breast cancer cells by binding to uPAR. Thereby, integrins situated adjacent to uPAR carry the signals into the cell, thus stimulating proliferation that is mediated via the MAPK pathway.

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Proliferation of a human epidermal tumor cell line stimulated by urokinase

Cited by 128 publications

References 20 publications

An autocrine role for urokinase in phorbol ester-mediated differentiation of myeloid cell lines.

An autocrine role for urokinase in phorbol ester-mediated differentiation of myeloid cell lines.

The urokinase receptor is required for human monocyte chemotaxis in vitro.

Urokinase-type plasminogen activator induces proliferation in breast cancer cells

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