FBXW7α attenuates inflammatory signalling by downregulating C/EBPδ and its target gene Tlr4.
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Version: Author's accepted manuscript
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State: Public
Version: Author's accepted manuscript
License: Not specified
Serval ID
serval:BIB_74C4B858B27D
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
FBXW7α attenuates inflammatory signalling by downregulating C/EBPδ and its target gene Tlr4.
Journal
Nature Communications
ISSN
2041-1723 (Electronic)
ISSN-L
2041-1723
Publication state
Published
Issued date
2013
Volume
4
Pages
1662
Language
english
Notes
Publication types: Journal ArticlePublication Status: ppublish
Abstract
Toll-like receptor 4 (Tlr4) has a pivotal role in innate immune responses, and the transcription factor CCAAT/enhancer binding protein delta (C/EBPδ, Cebpd) is a Tlr4-induced gene. Here we identify a positive feedback loop in which C/EBPδ activates Tlr4 gene expression in macrophages and tumour cells. In addition, we discovered a negative feedback loop whereby the tumour suppressor FBXW7α (FBW7, Cdc4), whose gene expression is inhibited by C/EBPδ, targets C/EBPδ for degradation when C/EBPδ is phosphorylated by GSK-3β. Consequently, FBXW7α suppresses Tlr4 expression and responses to the ligand lipopolysaccharide. FBXW7α depletion alone is sufficient to augment pro-inflammatory signalling in vivo. Moreover, as inflammatory pathways are known to modulate tumour biology, Cebpd null mammary tumours, which have reduced metastatic potential, show altered expression of inflammation-associated genes. Together, these findings reveal a role for C/EBPδ upstream of Tlr4 signalling and uncover a function for FBXW7α as an attenuator of inflammatory signalling.
Pubmed
Web of science
Open Access
Yes
Create date
06/05/2013 15:23
Last modification date
30/04/2021 7:11