Dexamethasone Inhibition of Tissue-Type Plasminogen Activator (tPA) Activity: Paradoxical Induction of Both tPA Antigen and Plasminogen Activator Inhibitor*

Gelehrter, Thomas D.; Sznycer-Laszuk, R; Zeheb, Ron; Cwikel, Bernard J.

doi:10.1210/mend-1-1-97

Cited by 47 publications

(27 citation statements)

References 25 publications

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“…The significance of the increase of tPA and uPA mRNA in osteoblasts when protein synthesis is inhibited is not yet clear. These results are relevant to other work that emphasizes the importance in the regulation of PA activity of the specific inhibitor, PAI-1 (Gelehrter et al, 1987;Seifert and Gelehrter, 1978;Andreasen et al, 1986Andreasen et al, , 1990Gelehrter, 1989, 1990). PAI-1 is bound to vitronectin in the extracellular matrix and retains its functional activity there (Mimuro et al, 1987;Sakata et al, 1988;Salonen et al, 1989), thereby limiting extracellular proteolysis.…”

Section: Discussionsupporting

confidence: 62%

Plasminogen activator regulation in osteoblasts: Parathyroid hormone inhibition of type‐1 plasminogen activator inhibitor and its mRNA

Fukumoto

Allan

Yee

et al. 1992

Journal Cellular Physiology

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In order to determine the mechanism by which parathyroid hormone (PTH) stimulates plasminogen activator (PA) activity in rat osteoblasts, we investigated the effect of human PTH(1-34) [hPTH(1-34)] on the synthesis of mRNAs for tissue-type PA (tPA), urokinase-type PA (uPA), and PA inhibitor-1 (PAI-1), and on release of PA activity and PAI-1 protein in both normal rat calvarial osteoblasts and UMR 106-01 osteogenic sarcoma cells. hPTH(1-34) (0.25-25 nM) decreased PAI-1 mRNA and protein, and increased PA activity in both cell types in a dose-dependent manner with ED50 of about 1 nM for both responses. Forskolin and isobutylmethylxanthine also stimulated PA activity and decreased PAI-1 protein and mRNA in both cell types. hPTH(1-34) did not show any consistent effect on tPA and uPA mRNA in calvarial osteoblasts, but a modest (two-fold) increase of both mRNAs was observed in UMR 106-01 cells treated with 25 nM hPTH(1-34). However, when protein synthesis was inhibited with 100 microM cycloheximide, the increase of tPA and uPA mRNA by hPTH(1-34) was enhanced in UMR 106-01 cells and became evident in calvarial osteoblasts. Fibrin autography also revealed that hPTH(1-34) increases tPA and uPA activity, especially after cycloheximide treatment in UMR 106-01 cells. These results strongly suggest that PTH increases PA activity predominantly by decreasing PAI-1 protein production through a cyclic adenosine monophosphate (cAMP)-dependent mechanism in rat osteoblasts. The reduction of PAI-1 protein by PTH results in enhanced action of both tPA and uPA, and would contribute to the specific roles of these PAs in bone.

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Section: Discussionsupporting

confidence: 62%

Plasminogen activator regulation in osteoblasts: Parathyroid hormone inhibition of type‐1 plasminogen activator inhibitor and its mRNA

Fukumoto

Allan

Yee

et al. 1992

Journal Cellular Physiology

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“…Cell Culture-HTC cells were maintained in monolayer cultures as described previously (5). In preparation for experiments, cells were plated in 60-mm tissue culture dishes and grown to confluence.…”

Section: Methodsmentioning

confidence: 99%

“…We have previously reported that incubation with the synthetic glucocorticoid, dexamethasone, decreases HTC cell tPA activity by increasing PAI-1 mRNA and protein 5-10-fold, an effect that is entirely explained by an increase in PAI-1 gene transcription (5)(6)(7). In contrast, these cells respond to cyclic nucleotides with a dramatic (Ն50-fold) increase in tPA activity that is primarily the result of a decrease in PAI-1 mRNA and protein (8).…”

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confidence: 97%

“…HTC rat hepatoma cells synthesize and secrete tissue-type plasminogen activator (tPA) and PAI-1 (5). We have previously reported that incubation with the synthetic glucocorticoid, dexamethasone, decreases HTC cell tPA activity by increasing PAI-1 mRNA and protein 5-10-fold, an effect that is entirely explained by an increase in PAI-1 gene transcription (5)(6)(7).…”

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confidence: 99%

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Cyclic Nucleotide Regulation of Type-1 Plasminogen Activator-Inhibitor mRNA Stability in Rat Hepatoma Cells

Heaton

Tillmann-Bogush

Leff

et al. 1998

Journal of Biological Chemistry

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Type-1 plasminogen activator-inhibitor (PAI-1) is a major physiologic inhibitor of plasminogen activation. Incubation of HTC rat hepatoma cells with the cyclic nucleotide analogue, 8-bromo-cAMP, causes a dramatic increase in tissue-type plasminogen activator activity secondary to a 90% decrease in PAI-1 mRNA. Although 8-bromo-cAMP causes a modest decrease in PAI-1 transcription, regulation is primarily the result of a 3-fold increase in the rate of PAI-1 mRNA degradation. To determine the cis-acting sequences required for cyclic nucleotide regulation, we have stably transfected HTC cells with chimeric genes containing sequences from the rat PAI-1 cDNA and the mouse ␤-globin gene and examined the effect of cyclic nucleotides on the decay rate of these transcripts. The mRNA transcribed from the ␤-globin gene is stable and not cyclic nucleotide-regulated, whereas the transcript from a construct containing the ␤-globin coding region and the PAI-1 3-untranslated region (UTR) is destabilized in the presence of 8-bromocAMP, suggesting that this response is mediated by sequences in the PAI-1 3-UTR. Analyses by deletion of sequences from this chimeric construct indicate that, whereas more than one region of the PAI-1 3-UTR can confer cyclic nucleotide responsiveness, the 3-most 134-nucleotide sequence alone is sufficient to do so. Insertion of PAI-1 sequences within the ␤-globin 3-UTR confirms that the 3-most 134 nucleotides of PAI-1 mRNA can confer cyclic nucleotide regulation of stability on a heterologous transcript, suggesting that this sequence may play a major role in hormonal regulation of PAI-1 mRNA stability.Eukaryotic gene expression is determined not only by the rate of gene transcription, but also by the rate at which the transcript is degraded. The steady state concentration of a particular mRNA, as well as the rate at which a new transcriptionally induced steady state is attained, is directly related to the message half-life (1, 2). Numerous recent studies have been aimed at understanding the role of specific sequences within the mRNA in determining basal transcript stability and have led to the identification of consensus sequences that confer stability or instability to a transcript (2, 3). Although it is known that many stimuli alter mRNA stability, little is known about either the cis-acting sequences in the RNA or the cellular factors involved in regulation of message decay.Plasminogen activators (PAs) 1 are serine proteases that are critical for thrombolysis and also play a key role in other physiological functions involving tissue remodeling. Plasminogen activator-inhibitors (PAIs) are specific inhibitors of PAs and are members of the serine protease inhibitor (serpin) family of proteins. Type-1 PAI (PAI-1) is a 50 kDa glycoprotein found in plasma, platelets, and a variety of cell types; its expression is regulated by growth factors, cytokines, and hormones, including agents that alter cellular cAMP levels (4).HTC rat hepatoma cells synthesize and secrete tissue-type plasminogen activator (tPA) and P...

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“…The expression of the components of the Pg-Pm system is modulated by the transcriptional regulation of a variety of hormones, such as corticosteroids [115,116] and gonadotrophins [117,118], and of cytokines [119][120][121][122] [140,141]. Since the cytokines and growth factors have many other effects on tumor growth and metastasis, it is difficult to interpret published findings if the components of the Pg-Pm system may act in concert with these factors.…”

Section: Regulatory Mechanismsmentioning

confidence: 99%

The plasminogen-plasmin system in malignancy

1992

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The study of the plasminogen-plasmin system has, in the past, contributed much to the understanding of fibrinolysis and thrombolysis. Attention is now focused on the role of the components of this system in many biologic functions. Findings of uPA, its receptor and its inhibitor in many tumor tissues and tumor cell lines, strongly implicate their involvement in tumor invasion, tumor cell proliferation and metastasis. The characteristics of the plasminogen activators, the uPA receptor and the plasminogen activator inhibitors as well as their expression and regulation in tumors and tumor cell lines are reviewed.

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Dexamethasone Inhibition of Tissue-Type Plasminogen Activator (tPA) Activity: Paradoxical Induction of Both tPA Antigen and Plasminogen Activator Inhibitor*

Cited by 47 publications

References 25 publications

Plasminogen activator regulation in osteoblasts: Parathyroid hormone inhibition of type‐1 plasminogen activator inhibitor and its mRNA

Plasminogen activator regulation in osteoblasts: Parathyroid hormone inhibition of type‐1 plasminogen activator inhibitor and its mRNA

Cyclic Nucleotide Regulation of Type-1 Plasminogen Activator-Inhibitor mRNA Stability in Rat Hepatoma Cells

The plasminogen-plasmin system in malignancy

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