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Título

Sterol Regulatory Element-binding Protein-2 Negatively Regulates Low Density Lipoprotein Receptor-related Protein Transcription

AutorLlorente-Cortés, Vicenta; Costales, Paula; Bernués, Jordi ; Camino-López, Sandra; Badimón, Lina
Palabras clavedown-regulation
LRP1
SREBP-2
Fecha de publicación2006
EditorAcademic Press
CitaciónJournal of Molecular Biology 359(4): 950-960 (2006)
ResumenLow density lipoprotein receptor-related protein (LRP1) binds aggregated LDL (agLDL) leading to a high intracellular cholesteryl ester (CE) accumulation. AgLDL up-regulates LRP1 expression concomitantly with an LDL receptor (LDLR) and sterol regulatory element binding protein (SREBP-2) down-regulation. The objectives were to investigate whether SREBP-2 regulates LRP1 transcription and determine the molecular mechanisms involved in the process. Down-regulation of active SREBP-2 by nLDL and agLDL led to LDLR down-regulation and LRP1 up-regulation. Enforced expression of an active form of SREBP-2 (SREBP-2-NT, amino acid residues 1-468) decreased LRP1 expression and LRP1 promoter (WT-LRP1) luciferase activity in a dose-dependent manner. LDL did not exert any significant effect on LRP1 promoter activity when a putative sterol regulatory element (SRE) (5-GTGGGGTGA-3′; +225 to +233) was mutated (SRE-MT-LRP1). SREBP-2 overexpression exerted stronger down-regulatory effects on WT-LRP1 than on SRE-MT-LRP1 promoter activity both in control, nLDL- and agLDL-exposed HeLa cells. Gel mobility shift assays showed that recombinant SREBP-2-NT protein (1-468) binds to a double-stranded LRP1 DNA fragment (215 to 245) containing a wild-type (wt) SRE sequence but not to a mutated SRE (mt) sequence (5-GAATTCGA-3′). Our results demonstrate that LDL stimulates LRP1 transcription and decreases SREBP-2 active form which negatively regulates LRP1 transcription. SRE sequence (+225 to +233) plays a pivotal role for the down-regulatory effect of SREBP-2 on LRP1 promoter activity. © 2006 Elsevier Ltd. All rights reserved.
Versión del editorhttp://dx.doi.org/10.1016/j.jmb.2006.04.008
URIhttp://hdl.handle.net/10261/112511
DOI10.1016/j.jmb.2006.04.008
Identificadoresdoi: 10.1016/j.jmb.2006.04.008
issn: 0022-2836
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