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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-alpha-induced transcription in monocytes

Citation

Mahony, D and Stringer, BW and Dickinson, JL and Antalis, TM, 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-alpha-induced transcription in monocytes, European Journal of Biochemistry, 256, (3) pp. 550-559. ISSN 0014-2956 (1998) [Refereed Article]

DOI: doi:10.1046/j.1432-1327.1998.2560550.x

Abstract

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-α (TNFα) 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 TNFα, and a MonoMac6 cell line which did not synthesise PAI-2 even after treatment with TNFα. 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 TNFα. 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.

Item Details

Item Type:Refereed Article
Research Division:Medical and Health Sciences
Research Group:Medical Biochemistry and Metabolomics
Research Field:Medical Biochemistry and Metabolomics not elsewhere classified
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Inherited Diseases (incl. Gene Therapy)
Author:Dickinson, JL (Associate Professor Joanne Dickinson)
ID Code:13934
Year Published:1998
Web of Science® Times Cited:5
Deposited By:Menzies Centre
Deposited On:1998-08-01
Last Modified:2011-08-08
Downloads:0

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