title: Fibromodulin suppresses nuclear factor-kappaB activity by inducing the delayed degradation of IKBA via a JNK-dependent pathway coupled to fibroblast apoptosis.
abstract: 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-β 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-β. 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-κB (NF-κB) activity, although those engineered to express Fmod constitutively exhibited significantly reduced NF-κB activity, suggesting that Fmod functions to inhibit NF-κB signaling. By monitoring alterations in the activation of NF-κB and the degradation of its inhibitor, IκBα, we demonstrate for the first time that Fmod contributes to the constitutive degradation of IκBα protein in 3T3-L1 fibroblasts. Mechanistically, we observed Fmod to delay the degradation of IκBα 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-κB activity and cell survival.
authors.affiliation: Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio 44106, USA.
authors.forename: Yong-Hun
authors.initials: YH
authors.lastname: Lee
authors.forename: William P
authors.initials: WP
authors.lastname: Schiemann
mesh_terms: D041721:3T3-L1 Cells; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002154:Calpain / Q000235:genetics / Q000378:metabolism; D047390:Casein Kinase II / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival / Q000502:physiology; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism*; D000071235:Fibromodulin; D005786:Gene Expression Regulation / Q000502:physiology; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D011509:Proteoglycans / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D016212:Transforming Growth Factor beta
chemical_list: D016326:Extracellular Matrix Proteins; C120769:Fbln5 protein, mouse; C000604332:Fmod protein, mouse; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D011509:Proteoglycans; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D000071235:Fibromodulin; D000072000:NF-KappaB Inhibitor alpha; D047390:Casein Kinase II; D048670:MAP Kinase Kinase 4; D002154:Calpain