The regulatory region of the human plasminogen activator inhibitor type-1 (PAI-1) gene

Riccio, Andrea; Lund, Leif R.; Sartorio, R.; Lania, Arturo; Anderasen, Peter A.; Danø, Keld; Blasi, Francesco

doi:10.1093/nar/16.7.2805

Cited by 80 publications

(29 citation statements)

References 60 publications

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“…9b). Although the PAI-1 promoter used in this study contained TGFb1 responsive elements (Riccio et al 1988(Riccio et al , 1992, it did not appear to have a DRE (GCGTG) motif to bind the AhR/Arnt complex. However, the gene for prostaglandin endoperoxide H synthase-2 was also induced by TCDD in a DRE-independent fashion with c-Src-mediated activation but still in an AhR-dependent manner (Vogel et al 2000).…”

Section: Discussionmentioning

confidence: 93%

2,3,7,8-Tetrachlorodibenzo- p -dioxin (TCDD) induces plasminogen activator inhibitor-1 through an aryl hydrocarbon receptor-mediated pathway in mouse hepatoma cell lines

Son

Rozman

2002

Archives of Toxicology

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2,3,7,8-Tetrachlorodibenzo- p-dioxin (TCDD), a ubiquitous environmental pollutant, elicits a variety of toxicities and is a well-known carcinogen. TCDD alters the expression of many genes including CYP1A1/2, CYP1B1, glutathione S-transferase Ya, aldehyde-3-dehydrogenase, NAD(P)H:quinone oxidoreductase, transforming growth factor (TGF)-alpha and TGF-beta. The present study was aimed at characterization of TCDD to induce plasminogen activator inhibitor-1 (PAI-1) in mouse hepatoma cell lines. A Hepa1c1c7 wild-type cell [H1(wt)], an aryl hydrocarbon receptor (AhR)-deficient mutant [H1(AhR(-))] and an AhR nuclear translocator (Arnt)-deficient mutant [H1(Arnt(-))] were used for this study. TCDD induced PAI-1 in H1(wt) cells, but not in H1(AhR(-)) and H1(Arnt(-)) mutants, indicating a functional role of the AhR-Arnt complex in this effect. Cycloheximide (CHX) treatment resulted in increased PAI-1 mRNA induction, indicating that this response to TCDD is a direct effect on transcription and not a secondary effect mediated by other TCDD-induced proteins. Transfection with PAI-1 promoter led to increased PAI-1 promoter activity in H1(wt) cells treated with TCDD, but no such effect occurred in H1(AhR(-)) or H1(Arnt(-)) cells, implying involvement of the AhR and Arnt. In addition, alpha-naphthoflavone and phenanthroline, two AhR antagonists, each blocked the enhancing effect of TCDD on PAI-1 promoter-coupled luciferase activity in H1(wt) cells. PAI-1 promoter deletion analysis indicated that TCDD-induced PAI-1 transcription was distinctly different from TGF-beta-dependent PAI-1 transcription, particularly in the region between -161 to +73. In summary, TCDD induced the PAI-1 gene directly via an AhR- and Arnt-dependent mechanism, which was distinctly different from TGF-beta-driven PAI-1 transcription.

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Section: Discussionmentioning

confidence: 93%

2,3,7,8-Tetrachlorodibenzo- p -dioxin (TCDD) induces plasminogen activator inhibitor-1 through an aryl hydrocarbon receptor-mediated pathway in mouse hepatoma cell lines

Son

Rozman

2002

Archives of Toxicology

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“…Comparison of 5%-flanking regions revealed two highly conserved elements with \80% identity in the proximal promoter (at −90 to − 25) and in a distal sequence (at −753 to − 512). The common features detected in the 5%-flanking regions of the PAI-1 genes of these three species are a consensus TATA box and sequences closely related to PEA3, AP1, CTF/NF-1, and Sp1 recognition sites [268][269][270]. The 5%-flanking region of the human PAI-1 gene contains four putative AP1-binding sites: −58 to −50 (TGAGTTCA), − 79 to − 72 (TGAGTGG), −662 to −656 (TGTATCA) and −721 to −714 (TGA-CACA), although none is identical to the consensus AP1 site [TGA(G/C)TCA] to which c-Fos/c-Jun heterodimers preferentially bind.…”

Section: The Tpa Genementioning

confidence: 99%

The plasminogen activator system: biology and regulation

Irigoyen

Muñoz‐Cánoves²,

Montero

et al. 1999

CMLS, Cell. Mol. Life Sci.

347

271

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The regulation of plasminogen activation involves genes for two plasminogen activators (tissue type and urokinase type), two specific inhibitors (type 1 and type 2), and a membrane-anchored urokinase-type plasminogen-activator-specific receptor. This system plays an important role in various biological processes involving extracellular proteolysis. Recent studies have revealed that the system, through interplay with integrins and the extracellular matrix protein vitronectin, is also involved in the regulation of cell migration and proliferation in a manner independent of proteolytic activity. The genes are expressed in many different cell types and their expression is under the control of diverse extracellular signals. Gene expression reflects the levels of the corresponding mRNA, which should be the net result of synthesis and degradation. Thus, modulation of mRNA stability is an important factor in overall regulation. This review summarizes current understanding of the biology and regulation of genes involved in plasminogen activation at different levels.

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“…The human PAI-1 promoter contains sequence stretches closely related to recognition sites for PEA3, AP1, AP2, Sp1, CTF/NF1, and Smad as well as cAMP and glucocorticoid-responsive elements (24,25). However, perfect consensus motifs for Rel protein binding are missing.…”

Section: Stable Overexpression Of ␣ V ␤ 3 In Human Ovarian Cancer Celmentioning

confidence: 99%

“…In earlier studies we have demonstrated that Rel proteins substantially contribute to elevated uPA gene expression in human ovarian cancer cells, thereby promoting the multiple functions of uPA during tumor growth and metastasis (22,23). The human PAI-1 promoter contains recognition sites for transcription factors including PEA3, AP1, AP2, and Sp1, whereas perfect consensus motifs for the binding of Rel proteins are lacking (24,25).…”

mentioning

confidence: 99%

Integrin αvβ3/Vitronectin Interaction Affects Expression of the Urokinase System in Human Ovarian Cancer Cells

Hapke¹,

Kessler²,

Prada³

et al. 2001

Journal of Biological Chemistry

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The urokinase type plasminogen activator (uPA), together with its receptor uPAR and the plasminogen activator inhibitor type-1 (PAI-1) plays a pivotal role during tumor invasion and metastasis. Integrins, via interaction with the extracellular matrix (ECM), control cell adhesion and motility. The two systems are functionally linked because uPAR and PAI-1 bind to the ECM component vitronectin (VN). Because integrin signaling alters gene expression patterns, we investigated whether the expression levels of uPA, uPAR, and PAI-1 are affected by ECM/integrin interactions. Expression of uPA, uPAR, and PAI-1 was significantly enhanced when human ovarian cancer cells (OV-MZ-6) were cultivated on fibronectin or collagen type IV. In contrast, VN induced down-regulation of uPA and uPAR while increasing PAI-1 by up to 4-fold. VN-dependent decrease of uPA protein was paralleled by a significant reduction of uPA promoter activity that was even more pronounced upon ␣ v ␤ 3 overexpression and depended on the presence of intact Rel protein-binding sites. The activity of Rel transcription factors was also significantly reduced upon ␣ v ␤ 3 -mediated cell adhesion to VN. The activity of the Rel-unresponsive PAI-1 promoter was up to 5-fold induced as a function of ␣ v ␤ 3 /VN interaction. Thus, the balance between available concentrations of uPA, uPAR, PAI-1, and integrins in human ovarian cancer cells might provide a switch within the regulation of their invasive phenotype.

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The regulatory region of the human plasminogen activator inhibitor type-1 (PAI-1) gene

Cited by 80 publications

References 60 publications

2,3,7,8-Tetrachlorodibenzo- p -dioxin (TCDD) induces plasminogen activator inhibitor-1 through an aryl hydrocarbon receptor-mediated pathway in mouse hepatoma cell lines

2,3,7,8-Tetrachlorodibenzo- p -dioxin (TCDD) induces plasminogen activator inhibitor-1 through an aryl hydrocarbon receptor-mediated pathway in mouse hepatoma cell lines

The plasminogen activator system: biology and regulation

Integrin αvβ3/Vitronectin Interaction Affects Expression of the Urokinase System in Human Ovarian Cancer Cells

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