Identification of a novel sterol-independent regulatory element in the human low density lipoprotein receptor promoter

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Abstract

The cytokine oncostatin M (OM) activates human low density lipoprotein receptor (LDLR) gene transcription through a sterol-independent mechanism. Previous studies conducted in our laboratory have narrowed the OM-responsive element to promoter region -52 to +13, which contains the repeat 3 and two TATA-like sequences. We now identify LDLR promoter region -17 to -1 as a sterol-independent regulatory element (SIRE) that is critically involved in OM-, transcription factor CCAAT/enhancer-binding protein (C/EBP)-, and second messenger cAMP-mediated activation of LDLR transcription. The SIRE sequence overlaps the previously described TATA-like element and consists of an active C/EBP-binding site (-17 to -9) and a functional cAMP-responsive element (CRE) (-8 to -1). We demonstrate that (a) mutations within either the C/EBP or CRE site have no impact on basal or cholesterol-mediated repression of LDLR transcription, but they completely abolish OM-mediated activation of LDLR transcription; (b) replacing the repeat 3 sequence that contains the Sp1- binding site with a yeast transcription factor GAL4-binding site in the LDLR promoter construct does not affect OM inducibility, thereby demonstrating that OM induction is mediated through the SIRE sequence in conjunction with a strong activator bound to the repeat 3 sequence; (c) electrophoretic mobility shift and supershift assays confirm the specific binding of transcription factors C/EBP and cAMP-responsive element-binding protein to the SIRE; (d) cotransfection of a human C/EBPβ expression vector (pEF-NFIL6) with the LDLR promoter construct pLDLR234 increases LDLR promoter activity; and (e) OM and dibutyryl cAMP synergistically activate LDLR transcription through this regulatory element. This study identifies, for the first time, a cis-acting regulatory element in the LDLR promoter that is responsible for sterol- independent regulation of LDLR transcription.

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Liu, J., Ahlborn, T. E., Briggs, M. R., & Kraemer, F. B. (2000). Identification of a novel sterol-independent regulatory element in the human low density lipoprotein receptor promoter. Journal of Biological Chemistry, 275(7), 5214–5221. https://doi.org/10.1074/jbc.275.7.5214

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