Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Binding of urokinase-type plasminogen activator (u-PA) to its receptor has been shown not only to focus proteolytic activity to the cell surface but also to exert a mitogenic effect on the human epidermal tumor cell line CCL 20.2. This report shows that u-PA is an autocrine mitogen in the human melanoma cell line GUBSB and that inhibition of receptor-bound u-PA by specific anti-u-PA antibodies causes a significant suppression of cell proliferation in this system. The GUBSB cell line secretes 70-80% of the u-PA in its active form and expresses high-affinity u-PA receptors with a Kd of 5.2 x 10(-10) M and 2.8 x 10(4) binding sites per cell. Approximately 70% of the u-PA receptors on these cells are occupied by endogenously secreted u-PA. Addition of the monoclonal anti-u-PA antibody MPW5UK (10 nM), directed against the active site of u-PA, twice daily to the cell cultures resulted in a significant decrease of [3H]thymidine incorporation by the tumor cells, whereas a 10 times higher concentration of the monoclonal antibody MPW4UK, which does not inhibit plasminogen activator activity of u-PA, was necessary to achieve the same effect. In addition, diisopropyl fluorophosphate-inactivated u-PA, in a concentration 50-fold higher than the concentration necessary to saturate the u-PA receptor (250 pM), decreased [3H]thymidine incorporation similarly to the specific antibody, proving that active u-PA is required for the mitogenic effect. Inhibition of endogenous u-PA production by cycloheximide reduced [3H]thymidine incorporation significantly; after addition of exogenous u-PA, [3H]thymidine incorporation increased again in the cycloheximide-treated cells. Therefore, inhibition of receptor-bound u-PA might represent a tool not only to inactivate cell-bound proteolytic activity, necessary for invasion, but also to exert a specific antiproliferative effect on certain tumor cells.
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PMID:Functional inhibition of endogenously produced urokinase decreases cell proliferation in a human melanoma cell line. 250 86

Several tumor cells secrete significantly increased amounts of the plasminogen activator urokinase, a trypsinlike serine protease, whose biological function in tumor biology is unclear. In this study we report that cells of the human epidermal tumor cell line CCL 20.2 express about 80,000 high-affinity urokinase receptors per cell that bind active as well as diisopropylfluorophosphate-treated high-molecular-weight (HMW) urokinase. Low-molecular-weight (LMW) urokinase is not bound to the receptor. Occupation of these receptors by active HMW urokinase stimulates cell proliferation independently in the presence of plasminogen in the culture medium. LMW urokinase has again no effect on cell proliferation. Calculated on a molar basis, this effect is about 28% of that of epidermal growth factor. Active HMW urokinase might therefore provide an autocrine receptor-mediated growth-promoting mechanism for tumor cells similar to those described for other growth factors.
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PMID:Proliferation of a human epidermal tumor cell line stimulated by urokinase. 303 46

The aim of this study was to investigate whether breast cancer growth in vivo could be due to a failure in the activation of TGF-beta 1, a growth factor which has been shown to affect the development of normal breast tissue. Tissue samples of 40 breast carcinomas and the normal adjacent tissue from 37 (henceforth referred to as 'adjacent tissue'), as well as 13 specimens of benign lesions, were included in this study. The specimens were used in vitro to produce conditioned medium (CM), and this was examined for TGF-beta 1 activity by measuring growth inhibition of the mink lung epithelial cell line CCL-64. Immunoblotting and electrophoresis were used to detect the presence of TGF-beta 1 in CM and homogenised tissue samples. We demonstrated that the majority of TGF-beta 1 in breast cancer conditioned medium was biologically active, in direct contrast to CM prepared from benign disease specimens. Furthermore, active TGF-beta 1 was also identified in CM prepared from adjacent tissue, suggesting an important early role for this growth factor in the spread of this disease. Three distinct breast cancer related (BCR) molecular weight species of TGF-beta 1 (12.5/25 kDa, 50 kDa and 95 kDa) were identified. Both the 50 kDa and 95 kDa bands immunoprecipitated by an anti-TGF-beta 1 antibody were also immunoreactive with anti-TGF-beta 1 binding protein antibodies suggesting that the 50 kDa band may comprise at least part of the previously described small latent complex of TGF-beta 1. However, using the CCL-64 cell assay, we were able to demonstrate that the 50 kDa TGF-beta 1 BCR protein was biologically active whereas the large (95 kDa) TGF-beta 1 BCR latent complex protein was not. Adjacent tissue was more likely to contain the 50 kDa form than the tumour tissues (P < 0.05). Similarly, the 50 kDa molecule was also more common in patients who had oestrogen receptor (ER) negative tumours (compared with ER positive patients; P < 0.05) and in those who had received tamoxifen treatment prior to surgery (P < 0.01). In all of these cases, the increase in the incidence of the small active complex form was accompanied by a decrease in the incidence of the high molecular weight complex (95 kDa). We confirmed that, in vitro, the 95 kDa TGF-beta 1 BCR can be proteolytically cleaved to yield a 50 kDa TGF-beta 1 BCR. Finally, we observed a correlation between the presence of the 50 kDa complex protein and reduced levels of plasminogen activator (PA), which was significant in ER negative patients (P < 0.05) and tamoxifen-pretreated patients (P < 0.01). This suggests that the secretion of this active TGF-beta 1 protein may provide breast tumours with a mechanism whereby they can escape oestrogen dependence, and may provide an explanation for the common problem of tamoxifen resistance.
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PMID:Multiple forms of TGF-beta 1 in breast tissues: a biologically active form of the small latent complex of TGF-beta 1. 891 Nov 19