A critical role for the Sp1-binding sites in the transforming growth factor-β-mediated inhibition of lipoprotein lipase gene expression in macrophages

Increasing evidence suggests that the cytokine transforming growth factor-β (TGF-β) inhibits the development of atherosclerosis. The lipoprotein lipase (LPL) enzyme expressed by macrophages has been implicated in the pathogenesis of atherosclerosis by stimulating the uptake of lipoprotein particles....

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Bibliographic Details
Published in:Nucleic acids research 2005-01, Vol.33 (5), p.1423-1434
Main Authors: Irvine, Scott A., Foka, Pelagia, Rogers, Sarah A., Mead, James R., Ramji, Dipak P.
Format: Article
Language:English
Subjects:
Animals
Base Sequence
Binding Sites
Cell Line
DNA-Binding Proteins - metabolism
Electrophoretic Mobility Shift Assay
Gene Expression Regulation, Enzymologic
Humans
Lipoprotein Lipase - biosynthesis
Lipoprotein Lipase - genetics
Macrophages - drug effects
Macrophages - enzymology
Mice
Molecular Sequence Data
Promoter Regions, Genetic
Sp1 Transcription Factor - metabolism
Sp3 Transcription Factor
Transcription Factors - metabolism
Transcription, Genetic - drug effects
Transforming Growth Factor beta - pharmacology
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Summary:Increasing evidence suggests that the cytokine transforming growth factor-β (TGF-β) inhibits the development of atherosclerosis. The lipoprotein lipase (LPL) enzyme expressed by macrophages has been implicated in the pathogenesis of atherosclerosis by stimulating the uptake of lipoprotein particles. Unfortunately, the action of TGF-β on the expression of LPL in macrophages remains largely unclear. We show that TGF-β inhibits LPL gene expression at the transcriptional level. Transient transfection assays reveal that the −31/+187 sequence contains the minimal TGF-β-responsive elements. Electrophoretic mobility shift assays show that Sp1 and Sp3 interact with two regions in the −31/+187 sequence. Mutations of these Sp1/Sp3 sites abolish the TGF-β-mediated suppression whereas multimers of the sequence impart the response to a heterologous promoter. TGF-β has no effect on the binding or steady-state polypeptide levels of Sp1 and Sp3. These results, therefore, suggest a novel mechanism for the TGF-β-mediated repression of LPL gene transcription that involves regulation of the action of Sp1 and Sp3.
ISSN:0305-1048
1362-4962
DOI:10.1093/nar/gki280