Plasminogen activator inhibitor 2. Isolation and characterization of the promoter region of the gene

Kruithof, Egbert K. O.; Cousin, E.

doi:10.1016/s0006-291x(88)80852-0

Cited by 31 publications

(6 citation statements)

References 16 publications

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“…The complete PAI-2 gene has only been isolated from the human genome [323]. Sequence information of 2 kb of the 5%-flanking region has been reported [324] and is available in the EMBL data bank under the accession number M22469. The human PAI-2 gene utilizes a TATA-dependent start site to initiate transcription.…”

Section: The Pai-2 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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Section: The Pai-2 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 location of DH3 at position Ϫ300 is consistent with these reported transcriptional activities in the proximal promoter. Within this region, three AP-1 sites, two AP-2 sites, and a cAMP-responsive element located between positions Ϫ544 and Ϫ97 have been identified [41]. Further upstream, the DH2 site centered at position Ϫ1920 corresponds well to the silencer element identified at position Ϫ1832 [12].…”

Section: Discussionmentioning

confidence: 91%

“…One of the major signalling pathways utilised by TNFA involves activation of the mitogen-activated-protein kinase cascade, which may in turn, activate transcription factors such as c-jun, c-fos and cAMP-response-element-binding protein/activating transcription factor (CREB/ATF). These factors can interact with DNA elements, such as AP-1 and CRE, found in the proximal promoter of PAI-2 [41] within the DH3 region. Signalling through direct activation of NFκB is also possible, although the proximal PAI-2 promoter does not contain a functional NFκBbinding site (data not shown).…”

Section: Discussionmentioning

confidence: 99%

DNase I hypersensitive sites in the 5′ flanking region of the human plasminogen activator inhibitor type 2 (PAI‐2) gene are associated with basal and tumor necrosis factor‐α‐induced transcription in monocytes

Mahony

Stringer

Dickinson

et al. 1998

European Journal of Biochemistry

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The plasminogen activator inhibitor type 2 (PAI-2) gene encodes a serine proteinase inhibitor (serpin) which is rapidly induced in response to the inflammatory cytokine, tumour necrosis factor-A (TNFA) in monocytes and macrophages. As an initial step towards understanding the molecular mechanisms underlying PAI-2 gene regulation in monocytes, we report here the analysis of the chromatin structure of 9.6 kb of 5′ flanking region of the human PAI-2 gene for potential cis-acting regulatory regions using DNase I hypersensitivity mapping. Sites sensitive to DNase I were mapped in two monocytic cell lines representative of early monocytic differentiation; U937 cells, which synthesise low constitutive levels of PAI-2 that were induced following treatment with TNFA, and a MonoMac6 cell line which did not synthesise PAI-2 even after treatment with TNFA. Six DNase I hypersensitive sites (DHS) were identified; three upstream of the transcription initiation site (DH1, DH2, DH3) and three downstream of the transcription initiation site which were contained within intron A (DH4, DH5) and the exon 2/intron B junction (DH6). Among these, one distally located DH site (DH2) disappeared in both cell lines following treatment with TNFA. Two DH sites (DH1, DH6) were absent in PAI-2-producing U937 cells, but were present in MonoMac6 cells, which did not produce PAI-2, indicating the possible involvement of negative regulatory elements in the suppression of PAI-2 gene expression. The results demonstrate the involvement of chromatin structure in transcriptional responsiveness of the PAI-2 gene promoter and identify several loci which may be key control regions for PAI-2 gene transcription.Keywords : DNase I hypersensitivity; plasminogen activator type-2 ; plasminogen activator ; monocytes ; TNFA.Plasminogen activator inhibitor type 2 (PAI-2), a member of the serine proteinase (serpin) family of proteinase inhibitors, is a major regulator of urokinase-type plasminogen activator (uPA) activity (reviewed in [1]). uPA controls the generation of plasmin, a broad spectrum serine proteinase involved in fibrinolysis, extracellular matrix remodelling, tumor metastasis and the activation of cytokines, receptors and growth factors in the extracellular milieu. The therapeutic potential of PAI-2 is underscored by laboratory studies which have demonstrated that tumour cell invasion is inhibited by recombinant PAI-2. While PAI-2 may be secreted as a glycosylated protein, the majority of PAI-2 synthesised by most cell types is not secreted, but found intracellularly, distributed in the cytosol [1]. A growing body of evidence suggests that intracellular PAI-2 mediates cell survival and apoptosis [2Ϫ5] through a uPA-independent mechanism. The dual localisation and corresponding functions of PAI-2 emphasise the potential importance of PAI-2 to both physiological and pathological processes.

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“…Similar studies in HT‐1080 fibrosarcoma cells demonstrated a transcriptional component following TNF‐mediated induction of PAI‐2 expression [14]. These studies led to an analysis of the PAI‐2 promoter [77,78]. DNase‐1 protection experiments indicated that the proximal region of the PAI‐2 promoter possessed a congested arrangement of cis ‐acting elements.…”

Section: Pai‐2 Gene Expression and Regulationmentioning

confidence: 89%

The undecided serpin

2005

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Plasminogen activator inhibitor type‐2 (PAI‐2) is a nonconventional serine protease inhibitor (serpin) with unique and tantalizing properties that is generally considered to be an authentic and physiological inhibitor of urokinase. However, the fact that only a small percentage of PAI‐2 is secreted has been a long‐standing argument for alternative roles for this serpin. Indeed, PAI‐2 has been shown to have a number of intracellular roles: it can alter gene expression, influence the rate of cell proliferation and differentiation, and inhibit apoptosis in a manner independent of urokinase inhibition. Despite these recent advances in defining the intracellular function of PAI‐2, it still remains one of the most mysterious and enigmatic members of the serpin superfamily.

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Plasminogen activator inhibitor 2. Isolation and characterization of the promoter region of the gene

Cited by 31 publications

References 16 publications

The plasminogen activator system: biology and regulation

The plasminogen activator system: biology and regulation

DNase I hypersensitive sites in the 5′ flanking region of the human plasminogen activator inhibitor type 2 (PAI‐2) gene are associated with basal and tumor necrosis factor‐α‐induced transcription in monocytes

The undecided serpin

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