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

被引：95

作者：

Balamurugan, Kuppusamy ^{[1
]}

Sharan, Shikha ^{[1
]}

Klarmann, Kimberly D. ^{[2
]}

Zhang, Youhong ^{[1
]}

Coppola, Vincenzo ^{[3
]}

Summers, Glenn H. ^{[4
]}

Roger, Thierry ^{[5
,6
]}

Morrison, Deborah K. ^{[1
]}

Keller, Jonathan R. ^{[2
]}

Sterneck, Esta ^{[1
]}

机构：

[1] Natl Canc Inst, Lab Cell & Dev Signalling, Frederick, MD 21702 USA

[2] SAIC Frederick Inc, Frederick Natl Lab Canc Res, Lab Canc Prevent, Basic Sci Program, Frederick, MD 21702 USA

[3] Ohio State Univ, Ctr Comprehens Canc, Wexner Med Ctr, Dept MVIMG, Columbus, OH 43210 USA

[4] NCI, FNLCR, Lab Anim Sci Program, SAIC Frederick, Frederick, MD 21702 USA

[5] CHU Vaudois, Dept Med, Infect Dis Serv, CH-1011 Lausanne, Switzerland

[6] Univ Lausanne, CH-1011 Lausanne, Switzerland

来源：

NATURE COMMUNICATIONS | 2013年 / 4卷

关键词：

TOLL-LIKE RECEPTORS; CCAAT/ENHANCER-BINDING PROTEINS; HYPOXIA-INDUCIBLE FACTORS; UBIQUITIN LIGASE; TUMOR-CELLS; IMMUNE-SYSTEM; EXPRESSION; CANCER; MACROPHAGES; METASTASIS;

D O I：

10.1038/ncomms2677

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

Toll-like receptor 4 (Tlr4) has a pivotal role in innate immune responses, and the transcription factor CCAAT/enhancer binding protein delta (C/EBP delta, Cebpd) is a Tlr4-induced gene. Here we identify a positive feedback loop in which C/EBP delta activates Tlr4 gene expression in macrophages and tumour cells. In addition, we discovered a negative feedback loop whereby the tumour suppressor FBXW7 alpha (FBW7, Cdc4), whose gene expression is inhibited by C/EBP delta, targets C/EBP delta for degradation when C/EBP delta is phosphorylated by GSK-3 beta. Consequently, FBXW7 alpha suppresses Tlr4 expression and responses to the ligand lipopolysaccharide. FBXW7 alpha 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/EBP delta upstream of Tlr4 signalling and uncover a function for FBXW7 alpha as an attenuator of inflammatory signalling.

引用

页数：12

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