Plasminogen activator inhibitor type‐2 Is a major protein induced in human fibroblasts and SK‐MEL‐109 melanoma cells by tumor necrosis factor

Abstract

Tumor necrosis factor (TNF) induces the synthesis of two proteins of Mr 42 and 36 kDa in human fibroblasts and SK-MEL-109 melanoma cells. To identify these proteins, a lambda gt10 cDNA library was prepared from the mRNA of TNF-treated SK-MEL-109 cells. By screening this library, we found a cDNA that preferentially hybridized to TNF-induced RNA. Hybrid-selected mRNA was translated into a protein of 42 kDa; cDNA sequence analysis followed by a comparison with other known protein sequences identified this protein with plasminogen activator inhibitor, type-2 (PAI-2). After removal of TNF, PAI-2 mRNA turned over rapidly, with an apparent half-life of approximately 2.5 h. Addition of dexamethasone increased the turnover of this mRNA, suggesting that the level of PAI-2 mRNA could be regulated post-transcriptionally by glucocorticoids. PAI-2 was not secreted, but accumulated in fibroblasts continuously treated with TNF.

Type‐2 plasminogen‐activator inhibitor is a substrate for trophoblast transglutaminase and Factor XIIIa

“…In such situations intracellular PAI-2 could be polymerized. Tumor-necrosis factor, capable of inducing apoptosis (Laster et al, 1988), also causes an increased expression of PAI-2 (Pytel et al, 1990) which appears to antagonize the cytolytic effect of the cytokine (Kumar and Baglioni, 1991). Increased PAI-2 expression also occurs in aged fibroblasts (Kumar et al, 1992), and in malignant cells transformed by the rus and src oncogenes (Cohen et al, 1989).…”

“…try, University of Aarhus, DK-8000 Aarhus C, Denmark cells, fibroblasts and melanoma cells (Scarpati and Sadler, 1989;Pytel et al, 1990;Johnson and Baglioni, 1990). It is present in the blood of pregnant women (Astedt et al, 1987) and in patients suffering from myeloid leukemia (Scherrer et al, 1991).…”

Plasminogen Activator Inhibitor Type 2 Contains mRNA Instability Elements within Exon 4 of the Coding Region

“…The discrepancy in the degree of mRNA production was suggestive of inducible stabilization of PAI-2 mRNA under these conditions. Subsequent studies have shown that the rate of PAI-2 mRNA decay can indeed be reduced by phorbol ester (15) and dioxin (16) or increased by dexamethasone (17).…”

Molecular Mechanisms Governing Tumor‐Necrosis‐Factor‐Mediated Regulation of Plasminogen‐Activator Inhibitor Type‐2 Gene Expression

“…Indeed, PAL2 is the most TNF-inducible protein observed in fibroblasts (Pytel et al, 1990;Beresini et al, 1988). In this report, we demonstrate that the PAI-2 gene promoter possesses two repressor regions ; one located distally between positions -1859 and -11 00, and one located proximally within a 40-bp region between positions -259 and -219.…”