Klf2 Suppresses Tgf-beta Signaling in Endothelium Through Induction of Smad7 and Inhibition of Ap-1.
From: Department of Medical Biochemistry, Academic Medical Center, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
Arteriosclerosis, thrombosis, and vascular biology
- Publish Date: Mar 2007
- ISSN: 1524-4636
- Volume: 27
- Issue: 3
- Pages: 532-9
- Medium: Internet
- Language: English
- Citation (JAMA): Boon Reinier A, Fledderus Joost O, Volger Oscar L, et al. Klf2 Suppresses Tgf-beta Signaling in Endothelium Through Induction of Smad7 and Inhibition of Ap-1.. Arterioscler. Thromb. Vasc. Biol. Mar 2007;27:532-9
Abstract
OBJECTIVE: The flow-responsive Kruppel-like factor 2 (KLF2) is crucial for maintaining endothelial cell quiescence. Here, we describe its detailed effects on transforming growth factor-beta (TGF-beta) signaling, which normally has proatherogenic effects on endothelium. METHODS AND RESULTS: In-depth analysis of genome-wide expression data shows that prolonged lentiviral-mediated overexpression of KLF2 in human umbilical vein endothelial cells (HUVECs) diminishes the expression of a large panel of established TGF-beta-inducible genes. Both baseline and TGF-beta-induced expression levels of plasminogen activator inhibitor 1 (PAI-1) and thrombospondin-1 are greatly diminished by KLF2. Using a combination of ectopic expression, small interfering RNA-mediated knockdown, and promoter activity assays, we show that KLF2 partly inhibits the phosphorylation and subsequent nuclear accumulation of Smad2, thereby suppressing the TGF-beta-induced Smad4-mediated transcriptional activity. This is achieved through TGF-beta-independent induction of inhibitory Smad7. Additionally, a full inhibition of TGF-beta signaling is functionally achieved through a simultaneous suppression of activator protein 1 (AP-1), which is an essential cofactor for TGF-beta-dependent transcription of many genes. CONCLUSIONS: The concerted mechanism by which KLF2 inhibits TGF-beta signaling through induction of inhibitory Smad7 and attenuation of AP-1 activity provides a novel mechanism by which KLF2 contributes to sustaining a quiescent, atheroprotective status of vascular endothelium.
Mesh Headings (Keywords): Blotting, Western, Cells, Cultured, Down-Regulation, Endothelial Cells, Gene Expression Regulation, Humans, Kruppel-Like Transcription Factors, Phosphorylation, RNA Interference, Signal Transduction, Smad7 Protein, Transcription Factor AP-1, Transforming Growth Factor beta, Umbilical Veins
Check for Full Text / PubMed Unique Identifier (PMID): 17194892
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