KLF11-mediated repression antagonizes Sp1/sterol-responsive element-binding protein-induced transcriptional activation of caveolin-1 in response to cholesterol signaling.
Cholesterol is a potent regulator of gene expression via a canonical pathway co-regulated by SREBP and Sp1. Here we establish the caveolin-1 gene promoter as a cell type-specific model for SREBP/Sp1 regulation whereby lipoprotein cholesterol depletion activates caveolin-1 transcription in endothelial type cells, but not in fibroblasts, both in vitro and in vivo. By extending this model, we describe a novel pathway distinct from the prototypical SREBP/Sp1 regulatory loop involving the Sp1-like protein, KLF11. Through a combination of RNA interference, chromatin immunoprecipitation assays, electrophoretic mobility shift assays, and reporter assays, we demonstrate that in the presence of cholesterol, KLF11 acts as a dominant repressor of the caveolin-1 gene. Mechanistically, cholesterol depletion results in displacement of KLF11 from an Sp1 site flanking an SRE, indicating that activation by SREBP/Sp1 requires antagonism of KLF11 repression. The displacement of KLF11 results from both a down-regulation of its expression and competition by Sp1 for DNA binding. Therefore, these studies identify a novel pathway whereby KLF11 repression is coordinated with Sp1/SREBP activation of cholesterol-dependent gene expression in a cell type-specific manner and outline the mechanisms by which these functions are achieved.
Cao
Sheng
S
Gastroenterology Research Unit and Tumor Biology Program, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA. cao.sheng@mayo.edu
Fernandez-Zapico
Martin E
ME
Jin
Dongzu
D
Puri
Vishwajeet
V
Cook
Tiffany A
TA
Lerman
Lilach O
LO
Zhu
Xiang-Yang
XY
Urrutia
Raul
R
Shah
Vijay
V
D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001483:Base Sequence; D002417:Cattle; D051242:Caveolin 1; D022461:Caveolins / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000502:physiology*; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D002855:Chromatography, Thin Layer; D017931:DNA Primers; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D047468:Immunoprecipitation; D012097:Repressor Proteins / Q000502:physiology*; D015398:Signal Transduction; D016329:Sp1 Transcription Factor / Q000502:physiology*; D014157:Transcription Factors / Q000037:antagonists & inhibitors*; D015533:Transcriptional Activation / Q000502:physiology*
D051017:Apoptosis Regulatory Proteins; C495540:CAV1 protein, human; D051242:Caveolin 1; D022461:Caveolins; D018797:Cell Cycle Proteins; D017931:DNA Primers; C115117:KLF11 protein, human; D012097:Repressor Proteins; D016329:Sp1 Transcription Factor; D014157:Transcription Factors; D002784:Cholesterol