| Glucocorticoids regulate arrestin gene expression and redirect the signaling profile of G protein-coupled receptors. | |
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MedLine Citation:
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PMID: 23045642 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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G protein-coupled receptors (GPCRs) compose the largest family of cell surface receptors and are the most common target of therapeutic drugs. The nonvisual arrestins, β-arrestin-1 and β-arrestin-2, are multifunctional scaffolding proteins that play critical roles in GPCR signaling. On binding of activated GPCRs at the plasma membrane, β-arrestins terminate G protein-dependent responses (desensitization) and stimulate β-arrestin-dependent signaling pathways. Alterations in the cellular complement of β-arrestin-1 and β-arrestin-2 occur in many human diseases, and their genetic ablation in mice has severe consequences. Surprisingly, however, the factors that control β-arrestin gene expression are poorly understood. We demonstrate that glucocorticoids differentially regulate β-arrestin-1 and β-arrestin-2 gene expression in multiple cell types. Glucocorticoids act via the glucocorticoid receptor (GR) to induce the synthesis of β-arrestin-1 and repress the expression of β-arrestin-2. Glucocorticoid-dependent regulation involves the recruitment of ligand-activated glucocorticoid receptors to conserved and functional glucocorticoid response elements in intron-1 of the β-arrestin-1 gene and intron-11 of the β-arrestin-2 gene. In human lung adenocarcinoma cells, the increased expression of β-arrestin-1 after glucocorticoid treatment impairs G protein-dependent activation of inositol phosphate signaling while enhancing β-arrestin-1-dependent stimulation of the MAPK pathway by protease activated receptor 1. These studies demonstrate that glucocorticoids redirect the signaling profile of GPCRs via alterations in β-arrestin gene expression, revealing a paradigm for cross-talk between nuclear and cell surface receptors and a mechanism by which glucocorticoids alter the clinical efficacy of GPCR-based drugs. |
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Authors:
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Robert H Oakley; Javier Revollo; John A Cidlowski |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Intramural Date: 2012-10-08 |
Journal Detail:
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Title: Proceedings of the National Academy of Sciences of the United States of America Volume: 109 ISSN: 1091-6490 ISO Abbreviation: Proc. Natl. Acad. Sci. U.S.A. Publication Date: 2012 Oct |
Date Detail:
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Created Date: 2012-10-24 Completed Date: 2013-01-07 Revised Date: 2013-04-23 |
Medline Journal Info:
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Nlm Unique ID: 7505876 Medline TA: Proc Natl Acad Sci U S A Country: United States |
Other Details:
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Languages: eng Pagination: 17591-6 Citation Subset: IM |
Affiliation:
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Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, US Department of Health and Human Services, Research Triangle Park, NC 27709, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Arrestins
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genetics* Cell Line, Tumor Chromatin Immunoprecipitation Gene Expression Regulation / drug effects* Glucocorticoids / pharmacology* Humans RNA, Messenger / genetics Receptors, G-Protein-Coupled / metabolism* Reverse Transcriptase Polymerase Chain Reaction Signal Transduction / drug effects* |
| Chemical | |
Reg. No./Substance:
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0/Arrestins; 0/Glucocorticoids; 0/RNA, Messenger; 0/Receptors, G-Protein-Coupled; 0/beta-arrestin |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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