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Transcriptional regulation of human dual specificity protein phosphatase 1 (DUSP1) gene by glucocorticoids

Shipp, LE and Lee, JV and Yu, CY and Pufall, M and Zhang, P and Scott, DK and Wang, JC (2010) Transcriptional regulation of human dual specificity protein phosphatase 1 (DUSP1) gene by glucocorticoids. PLoS ONE, 5 (10).

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Background: Glucocorticoids are potent anti-inflammatory agents commonly used to treat inflammatory diseases. They convey signals through the intracellular glucocorticoid receptor (GR), which upon binding to ligands, associates with genomic glucocorticoid response elements (GREs) to regulate transcription of associated genes. One mechanism by which glucocorticoids inhibit inflammation is through induction of the dual specificity phosphatase-1 (DUSP1, a.k.a. mitogen-activated protein kinase phosphatase-1, MKP-1) gene. Methodology/Principal Findings: We found that glucocorticoids rapidly increased transcription of DUSP1 within 10 minutes in A549 human lung adenocarcinoma cells. Using chromatin immunoprecipitation (ChIP) scanning, we located a GR binding region between 21421 and 21118 upstream of the DUSP1 transcription start site. This region is active in a reporter system, and mutagenesis analyses identified a functional GRE located between 21337 and 21323. We found that glucocorticoids increased DNase I hypersensitivity, reduced nucleosome density, and increased histone H3 and H4 acetylation within genomic regions surrounding the GRE. ChIP experiments showed that p300 was recruited to the DUSP1 GRE, and RNA interference experiments demonstrated that reduction of p300 decreased glucocorticoid-stimulated DUSP1 gene expression and histone H3 hyperacetylation. Furthermore, overexpression of p300 potentiated glucocorticoid-stimulated activity of a reporter gene containing the DUSP1 GRE, and this coactivation effect was compromised when the histone acetyltransferase domain was mutated. ChIP-reChIP experiments using GR followed by p300 antibodies showed significant enrichment of the DUSP1 GRE upon glucocorticoid treatment, suggesting that GR and p300 are in the same protein complex recruited to the DUSP1 GRE. Conclusions/Significance: Our studies identified a functional GRE for the DUSP1 gene. Moreover, the transcriptional activation of DUSP1 by glucocorticoids requires p300 and a rapid modification of the chromatin structure surrounding the GRE. Overall, understanding the mechanism of glucocorticoid-induced DUSP1 gene transcription could provide insights into therapeutic approaches against inflammatory diseases. © 2010 Shipp et al.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Shipp, LE
Lee, JV
Yu, CY
Pufall, M
Zhang, P
Scott, DK
Wang, JC
ContributionContributors NameEmailPitt UsernameORCID
Date: 17 November 2010
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 5
Number: 10
DOI or Unique Handle: 10.1371/journal.pone.0013754
Refereed: Yes
MeSH Headings: Acetylation; Base Sequence; Cell Line, Tumor; Chromatin Immunoprecipitation; DNA Primers; Dexamethasone--pharmacology; Dual Specificity Phosphatase 1--genetics; Dual Specificity Phosphatase 1--metabolism; Gene Expression Regulation, Enzymologic--drug effects; Histones--metabolism; Humans; Mutagenesis, Site-Directed; Polymerase Chain Reaction; Promoter Regions, Genetic; Transcription, Genetic--drug effects
Other ID: NLM PMC2966426
PubMed Central ID: PMC2966426
PubMed ID: 21060794
Date Deposited: 22 Aug 2012 21:02
Last Modified: 02 Feb 2019 21:55


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