| First Author | Balamurugan K | Year | 2013 |
| Journal | Nat Commun | Volume | 4 |
| Pages | 1662 | PubMed ID | 23575666 |
| Mgi Jnum | J:325933 | Mgi Id | MGI:6210575 |
| Doi | 10.1038/ncomms2677 | Citation | Balamurugan K, et al. (2013) FBXW7alpha attenuates inflammatory signalling by downregulating C/EBPdelta and its target gene Tlr4. Nat Commun 4:1662 |
| abstractText | 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. |
