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PMID: 17349961 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

An essential function of the SRC-3 coactivator in suppression of cytokine mRNA translation and inflammatory response.

Molecular cell ·Vol. 25 ·No. 5 ·2007-03-09 ·Pages 765-78

Yu C, York B, Wang S, Feng Q, Xu J, O'Malley BW

Abstract

Steroid receptor coactivator-3 (SRC-3) is a transcriptional coactivator for nuclear receptors and other transcription factors. Although multiple physiological roles of SRC-3 have been revealed, its involvement in the inflammatory process remains unclear. Herein we show that SRC-3(-/-) mice are markedly hypersensitive to LPS-induced endotoxic shock. In response to LPS, SRC-3(-/-) macrophages produce significantly more proinflammatory cytokines such as TNF-alpha, IL-6, and IL-1beta than wild-type controls, although they express similar amounts of cytokine mRNAs, suggesting that SRC-3 can exert effects at translational levels. Increased heavy polysome-associated TNF-alpha and IL-1beta mRNAs in SRC-3(-/-) macrophages implicate SRC-3 as a translational repressor. SRC-3 may cooperate with other translational repressors such as TIA-1 and TIAR to regulate cytokine mRNA translation. Collectively, our studies reveal an essential function of SRC-3 as a coordinator of inflammatory mRNA translation and as a physiologic protective factor against the lethal endotoxic shock triggered by an acute inflammatory response.

MeSH Terms
Animals Cytokines/blood,genetics,metabolism Female HeLa Cells Histone Acetyltransferases/metabolism Humans Inflammation Lipopolysaccharides/pharmacology Macrophages, Peritoneal/cytology,drug effects Male Mice Nuclear Receptor Coactivator 3 Protein Binding/drug effects Protein Biosynthesis/drug effects,genetics RNA-Binding Proteins/metabolism Receptors, Glucocorticoid/metabolism Repressor Proteins/metabolism Shock, Septic/chemically induced,pathology T-Cell Intracellular Antigen-1 Trans-Activators/metabolism Tumor Necrosis Factor-alpha/genetics,metabolism
Chemicals
Cytokines Lipopolysaccharides RNA-Binding Proteins Receptors, Glucocorticoid Repressor Proteins T-Cell Intracellular Antigen-1 Tia1 protein, mouse Tial1 protein, mouse Trans-Activators Tumor Necrosis Factor-alpha Histone Acetyltransferases NCOA3 protein, human Ncoa3 protein, mouse Nuclear Receptor Coactivator 3
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Yu Chundong
Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
York Brian
Wang Shu
Feng Qin
Xu Jianming
O'Malley Bert W
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Article Info
Journal
Molecular cell
Abbr.
Mol Cell
ISSN
1097-2765
DOI
10.1016/j.molcel.2007.01.025
Published
2007-03-09
Pages
765-78
Language
English
Region
United States
NLM ID
9802571
PMCID
PMC1864954
Subset
IM
Grants
NIDDK NIH HHS · P01 DK059820 · United States
NIDDK NIH HHS · U19 DK062434 · United States
NICHD NIH HHS · R01 HD008188 · United States
NIGMS NIH HHS · F32 GM072235 · United States
NIGMS NIH HHS · F32 GM 072235 · United States
Corrections
CommentIn
PMID: 17386257
External Links
PubMed source DOI: 10.1016/j.molcel.2007.01.025 PMC Full Text View journal details
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