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FBXW7α attenuates inflammatory signalling by downregulating C/EBPδ and its target gene Tlr4

Author

Listed:
  • Kuppusamy Balamurugan

    (Laboratory of Cell and Developmental Signalling, National Cancer Institute-Frederick, PO Box B, Frederick, Maryland 21702-1201, USA)

  • Shikha Sharan

    (Laboratory of Cell and Developmental Signalling, National Cancer Institute-Frederick, PO Box B, Frederick, Maryland 21702-1201, USA)

  • Kimberly D. Klarmann

    (Basic Science Program, SAIC-Frederick, Inc., Laboratory of Cancer Prevention, Frederick National Laboratory for Cancer Research, PO Box B, Frederick, Maryland 21702-1201, USA)

  • Youhong Zhang

    (Laboratory of Cell and Developmental Signalling, National Cancer Institute-Frederick, PO Box B, Frederick, Maryland 21702-1201, USA)

  • Vincenzo Coppola

    (Wexner Medical Center, Ohio State University-Comprehensive Cancer Center, Ohio State University-CCC, 988 Biological Research Tower 460 West 12th Avenue)

  • Glenn H. Summers

    (Laboratory Animal Sciences Program, SAIC-Frederick, NCI, FNLCR)

  • Thierry Roger

    (Infectious Diseases Service, Centre Hospitalier Universitaire Vaudois and University of Lausanne)

  • Deborah K. Morrison

    (Laboratory of Cell and Developmental Signalling, National Cancer Institute-Frederick, PO Box B, Frederick, Maryland 21702-1201, USA)

  • Jonathan R. Keller

    (Basic Science Program, SAIC-Frederick, Inc., Laboratory of Cancer Prevention, Frederick National Laboratory for Cancer Research, PO Box B, Frederick, Maryland 21702-1201, USA)

  • Esta Sterneck

    (Laboratory of Cell and Developmental Signalling, National Cancer Institute-Frederick, PO Box B, Frederick, Maryland 21702-1201, USA)

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.

Suggested Citation

  • Kuppusamy Balamurugan & Shikha Sharan & Kimberly D. Klarmann & Youhong Zhang & Vincenzo Coppola & Glenn H. Summers & Thierry Roger & Deborah K. Morrison & Jonathan R. Keller & Esta Sterneck, 2013. "FBXW7α attenuates inflammatory signalling by downregulating C/EBPδ and its target gene Tlr4," Nature Communications, Nature, vol. 4(1), pages 1-12, June.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms2677
    DOI: 10.1038/ncomms2677
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