title: FBXW7α attenuates inflammatory signalling by downregulating C/EBPδ and its target gene Tlr4.
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.
authors.affiliation: Laboratory of Cell and Developmental Signalling, National Cancer Institute-Frederick, PO Box B, Frederick, Maryland 21702-1201, USA.
authors.forename: Kuppusamy
authors.initials: K
authors.lastname: Balamurugan
authors.forename: Shikha
authors.initials: S
authors.lastname: Sharan
authors.forename: Kimberly D
authors.initials: KD
authors.lastname: Klarmann
authors.forename: Youhong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Coppola
authors.forename: Glenn H
authors.initials: GH
authors.lastname: Summers
authors.forename: Thierry
authors.initials: T
authors.lastname: Roger
authors.forename: Deborah K
authors.initials: DK
authors.lastname: Morrison
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Keller
authors.forename: Esta
authors.initials: E
authors.lastname: Sterneck
mesh_terms: D000818:Animals; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000502:physiology*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D044783:F-Box Proteins / Q000235:genetics / Q000502:physiology*; D000073979:F-Box-WD Repeat-Containing Protein 7; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics; D007249:Inflammation / Q000235:genetics / Q000503:physiopathology*; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000502:physiology*
chemical_list: C497253:Cebpd protein, mouse; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513272:Fbxw7 protein, mouse; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D051743:CCAAT-Enhancer-Binding Protein-delta; D044767:Ubiquitin-Protein Ligases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3