期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 286, 期 8, 页码 6414-6422出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M110.168682
关键词
-
资金
- National Institutes of Health [CA129359]
- Department of Defense [BC084651]
- Komen Foundation [BCTR0706967]
Fibulin-5 (FBLN5) belongs to the Fibulin family of secreted extracellular matrix proteins, and our laboratory first established FBLN5 as a novel target for TGF-beta in fibroblasts and endothelial cells. To better understand the pathophysiology of FBLN5, we carried out microarray analysis to identify fibroblast genes whose expressions were regulated by FBLN5 and TGF-beta. In doing so, we identified fibromodulin (Fmod) as a novel target gene of FBLN5, and we validated the differential expression of Fmod and 12 other FBLN5-regulated genes by semi-quantitative real time PCR. Fmod belongs to the small leucine-rich family of proteoglycans, which are important constituents of mammalian extracellular matrices. Interestingly, parental 3T3-L1 fibroblasts displayed high levels of nuclear factor-kappa B (NF-kappa B) activity, although those engineered to express Fmod constitutively exhibited significantly reduced NF-kappa B activity, suggesting that Fmod functions to inhibit NF-kappa B signaling. By monitoring alterations in the activation of NF-kappa B and the degradation of its inhibitor, I kappa B alpha, we demonstrate for the first time that Fmod contributes to the constitutive degradation of I kappa B alpha protein in 3T3-L1 fibroblasts. Mechanistically, we observed Fmod to delay the degradation of I kappa B alpha by promoting the following: (i) activation of c-Jun N-terminal kinase; (ii) inhibition of calpain and casein kinase 2 activity; and (iii) induction of fibroblast apoptosis. Taken together, our study identified a novel function for Fmod in directing extracellular signaling, particularly the regulation of NF-kappa B activity and cell survival.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据