Document Detail


Glucocorticoids regulate arrestin gene expression and redirect the signaling profile of G protein-coupled receptors.
MedLine Citation:
PMID:  23045642     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Robert H Oakley; Javier Revollo; John A Cidlowski
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Intramural     Date:  2012-10-08
Journal Detail:
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:
Created Date:  2012-10-24     Completed Date:  2013-01-07     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  17591-6     Citation Subset:  IM    
Affiliation:
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.
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MeSH Terms
Descriptor/Qualifier:
Arrestins / 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:
0/Arrestins; 0/Glucocorticoids; 0/RNA, Messenger; 0/Receptors, G-Protein-Coupled; 0/beta-arrestin
Comments/Corrections

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