PMID- 23575666
OWN - NLM
STAT- MEDLINE
DCOM- 20131022
LR  - 20211021
IS  - 2041-1723 (Electronic)
IS  - 2041-1723 (Linking)
VI  - 4
DP  - 2013
TI  - FBXW7alpha attenuates inflammatory signalling by downregulating C/EBPdelta and its target 
      gene Tlr4.
PG  - 1662
LID - 10.1038/ncomms2677 [doi]
AB  - Toll-like receptor 4 (Tlr4) has a pivotal role in innate immune responses, and 
      the transcription factor CCAAT/enhancer binding protein delta (C/EBPdelta, Cebpd) is 
      a Tlr4-induced gene. Here we identify a positive feedback loop in which C/EBPdelta 
      activates Tlr4 gene expression in macrophages and tumour cells. In addition, we 
      discovered a negative feedback loop whereby the tumour suppressor FBXW7alpha (FBW7, 
      Cdc4), whose gene expression is inhibited by C/EBPdelta, targets C/EBPdelta for 
      degradation when C/EBPdelta is phosphorylated by GSK-3beta. Consequently, FBXW7alpha 
      suppresses Tlr4 expression and responses to the ligand lipopolysaccharide. FBXW7alpha 
      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/EBPdelta upstream of Tlr4 signalling and uncover a function for FBXW7alpha as 
      an attenuator of inflammatory signalling.
FAU - Balamurugan, Kuppusamy
AU  - Balamurugan K
AD  - Laboratory of Cell and Developmental Signalling, National Cancer 
      Institute-Frederick, PO Box B, Frederick, Maryland 21702-1201, USA.
FAU - Sharan, Shikha
AU  - Sharan S
FAU - Klarmann, Kimberly D
AU  - Klarmann KD
FAU - Zhang, Youhong
AU  - Zhang Y
FAU - Coppola, Vincenzo
AU  - Coppola V
FAU - Summers, Glenn H
AU  - Summers GH
FAU - Roger, Thierry
AU  - Roger T
FAU - Morrison, Deborah K
AU  - Morrison DK
FAU - Keller, Jonathan R
AU  - Keller JR
FAU - Sterneck, Esta
AU  - Sterneck E
LA  - eng
GR  - HHSN261200800001C/RC/CCR NIH HHS/United States
GR  - HHSN261200800001E/CA/NCI NIH HHS/United States
GR  - ZIA BC010307-11/Intramural NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, N.I.H., Intramural
PL  - England
TA  - Nat Commun
JT  - Nature communications
JID - 101528555
RN  - 0 (Cebpd protein, mouse)
RN  - 0 (F-Box Proteins)
RN  - 0 (F-Box-WD Repeat-Containing Protein 7)
RN  - 0 (Fbxw7 protein, mouse)
RN  - 0 (Hif1a protein, mouse)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (RNA, Messenger)
RN  - 0 (Tlr4 protein, mouse)
RN  - 0 (Toll-Like Receptor 4)
RN  - 142662-43-9 (CCAAT-Enhancer-Binding Protein-delta)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
RN  - EC 2.7.11.1 (GSK3B protein, human)
RN  - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta)
RN  - EC 2.7.11.1 (Gsk3b protein, mouse)
RN  - EC 2.7.11.26 (Glycogen Synthase Kinase 3)
SB  - IM
MH  - Animals
MH  - CCAAT-Enhancer-Binding Protein-delta/*physiology
MH  - Cell Line, Tumor
MH  - *Down-Regulation
MH  - F-Box Proteins/genetics/*physiology
MH  - F-Box-WD Repeat-Containing Protein 7
MH  - Glycogen Synthase Kinase 3/metabolism
MH  - Glycogen Synthase Kinase 3 beta
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/genetics
MH  - Inflammation/genetics/*physiopathology
MH  - Mice
MH  - RNA, Messenger/genetics
MH  - Signal Transduction/*physiology
MH  - Toll-Like Receptor 4/*physiology
MH  - Ubiquitin-Protein Ligases/genetics/*physiology
PMC - PMC3625980
MID - NIHMS451081
EDAT- 2013/04/12 06:00
MHDA- 2013/10/23 06:00
PMCR- 2013/10/09
CRDT- 2013/04/12 06:00
PHST- 2012/09/28 00:00 [received]
PHST- 2013/02/28 00:00 [accepted]
PHST- 2013/04/12 06:00 [entrez]
PHST- 2013/04/12 06:00 [pubmed]
PHST- 2013/10/23 06:00 [medline]
PHST- 2013/10/09 00:00 [pmc-release]
AID - ncomms2677 [pii]
AID - 10.1038/ncomms2677 [doi]
PST - ppublish
SO  - Nat Commun. 2013;4:1662. doi: 10.1038/ncomms2677.