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, Timothy J.; Stringer, Brett W.; Dickinson, Joanne L.; Antalis, Toni M.

doi:10.1046/j.1432-1327.1998.2560550.x

Cited by 3 publications

(3 citation statements)

References 45 publications

(55 reference statements)

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“…Molecular mechanisms controlling induction of PAI‐2 gene transcription in response to TNFα are not understood. In monocytic cells, changes in chromatin structure, as detected by DNase I hypersensitivity analysis, accompanied the response to TNFα, suggesting a release of transcriptional repression, although a positive regulatory stimulus for transcriptional induction has not been identified [17]. An additional TNFα repressor element has been reported in the proximal PAI‐2 promoter at position −216, the mutation of which allows induction of PAI‐2 in response to TNFα[18].…”

Section: Homologies Between Pai‐2 Nf‐κb‐like Motifs and Selected Funcmentioning

confidence: 99%

“…Two AP‐1‐like elements and a cAMP responsive element in the proximal promoter region are important for induction in response to the protein kinase C activator, 4β‐phorbol 12‐myristate 13‐acetate [13], and additional regulatory elements outside of this region appear to modulate these responses to control cell‐specific and tissue‐specific expression [10,14]. Within 8.8 kb of the PAI‐2 5′‐flanking sequence and first intron, three nuclear protein binding regions have been identified [14], with several of these corresponding to transcriptionally active regions mapped by DNase I hypersensitivity analysis of the intact chromatin structure of the PAI‐2 gene in vivo [17].…”

Section: Homologies Between Pai‐2 Nf‐κb‐like Motifs and Selected Funcmentioning

confidence: 99%

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Plasminogen activator inhibitor type‐2 (PAI‐2) gene transcription requires a novel NF‐κB‐like transcriptional regulatory motif

Mahony

Kalionis

Antalis

1999

European Journal of Biochemistry

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Induction of human plasminogen activator inhibitor type‐2 (PAI‐2) gene transcription is the response of macrophages to inflammatory stimuli, such as the pleiotropic cytokine, tumour necrosis factor‐α (TNFα). Here we have examined whether PAI‐2 gene transcription in response to TNFα may be mediated through a regulatory pathway involving the transcription factor, NF‐κB. We have tested the function of two potential NF‐κB‐like sites present in the PAI‐2 proximal promoter for responsiveness to TNFα using chloramphenicol acetyl transferase reporter gene deletion and mutation analyses. While no evidence was found for TNFα regulation of the PAI‐2 gene through either of these two sites, one of the NF‐κB‐like motifs, transcriptional regulatory motif (TRM), present at position −400 was found to be essential for constitutive PAI‐2 transcription, as mutation of this motif abolished basal PAI‐2 promoter activity in both monocyte‐like U937 cells and HT1080 fibrosarcoma cells. Competition electrophoretic mobility shift assays identified four TRM‐binding proteins present in U937, HT1080 and HeLa cell extracts, which bound to this motif but were not components of the NF‐κB regulatory complex. Expression screening of a HeLa cell cDNA library using the −400 TRM as a probe identified two cDNAs encoding partial peptides which specifically bound the TRM motif. DNA sequence analysis revealed that one cDNA was novel, and the second cDNA encoded exon 5 of the nephroblastoma overexpressed (novH) proto‐oncogene, suggesting a new role for this peptide in gene regulation. Taken together, these findings identify a new regulatory element required for constitutive PAI‐2 transcription, and identify potential DNA‐binding proteins associated with this element that may play a role in PAI‐2 gene regulation.

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Section: Homologies Between Pai‐2 Nf‐κb‐like Motifs and Selected Funcmentioning

confidence: 99%

Section: Homologies Between Pai‐2 Nf‐κb‐like Motifs and Selected Funcmentioning

confidence: 99%

Plasminogen activator inhibitor type‐2 (PAI‐2) gene transcription requires a novel NF‐κB‐like transcriptional regulatory motif

Mahony

Kalionis

Antalis

1999

European Journal of Biochemistry

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“…Notwithstanding the important contribution of transcriptional control (14,15) to the regulation of PAI-2 expression, significant regulation also occurs at the post-transcriptional level, most notably at the level of PAI-2 mRNA stability (16,17). Post-transcriptional regulation of gene expression has proven to be a particularly important component in the global control of gene regulation.…”

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confidence: 99%

Inherent Instability of Plasminogen Activator Inhibitor Type 2 mRNA Is Regulated by Tristetraprolin

Stasinopoulos

Leedman³

et al. 2003

Journal of Biological Chemistry

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Plasminogen activator inhibitor type 2 (PAI-2) is a serine protease inhibitor that is subject to regulation at the post-transcriptional level. At least two mRNA instability elements reside within the PAI-2 transcript; one in the coding region and another within the 3-untranslated region (UTR). For the latter, a functional AU-rich motif (ARE) has been identified that provides a binding site for a number of cellular proteins, including the mRNA stability protein, HuR. In this study, we used the yeast three-hybrid system to screen a human leukocyte cDNA library to identify other proteins that associate with the PAI-2 ARE. This screen identified tristetraprolin (TTP) as a PAI-2 mRNA ARE-binding protein. UV cross-linking and immunoprecipitation experiments showed that TTP expressed in HEK293 cells could associate with the PAI-2 ARE in vitro. Co-transfection of plasmids expressing TTP and PAI-2 in HEK293 cells resulted in an increase in the decay rate of PAI-2 mRNA and loss of PAI-2 protein in a process that was dependent upon the PAI-2 3-UTR. The 29-nt PAI-2 AU-rich element alone was also capable of conferring TTP-dependent mRNA instability to a reporter transcript. The extent of PAI-2 mRNA stability was remarkably sensitive to TTP since TTP-dependent PAI-2 mRNA decay occurred at TTP levels that were below Western blot detection limits. This study identifies TTP as a functional PAI-2 ARE-binding protein that modulates the post-transcriptional regulation of the PAI-2 gene.

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The Inhibitors of the Fibrinolytic System

Kruithof¹

2001

Handbook of Experimental Pharmacology

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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

Cited by 3 publications

References 45 publications

Plasminogen activator inhibitor type‐2 (PAI‐2) gene transcription requires a novel NF‐κB‐like transcriptional regulatory motif

Plasminogen activator inhibitor type‐2 (PAI‐2) gene transcription requires a novel NF‐κB‐like transcriptional regulatory motif

Inherent Instability of Plasminogen Activator Inhibitor Type 2 mRNA Is Regulated by Tristetraprolin

The Inhibitors of the Fibrinolytic System

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