Regulation of human CETP gene expression:  Role of SP1 and SP3 transcription factors at promoter sites-690,629 and-37

doi:10.1194/jlr.M200425-JLR200

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A more recent version of this article appeared on July 1, 2003

Papers In Press, published online ahead of print May 1, 2003
J. Lipid Res., doi:10.1194/jlr.M200425-JLR200

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Submitted on October 28, 2002
Revised on April 22, 2003
Accepted on April 22, 2003

Regulation of human CETP gene expression: Role of SP1 and SP3 transcription factors at promoter sites-690,629 and-37

Wilfried Le Goff, Maryse Guérin, Laure Petit, M. John Chapman, and Joëlle Thillet

INSERM U551, Hôpital de la Pitié, Paris 75651

Corresponding Author: chapman{at}chups.jussieu.fr

The cholesteryl ester transfer protein (CETP) is a key factor in plasma reverse cholesterol transport and is implicated in the pathophysiology of atherogenic dyslipidemia. Variation observed in plasma CETP mass and activity in both normolipidemic and in dyslipidemic individuals may reflect differences in CETP gene expression. We evaluated the respective roles of the Sp1 and Sp3 transcription factors on the promoter activity of the human CETP gene at a new Sp1/Sp3 site identified at position -690 and at two previously described Sp1/Sp3 sites at positions -37 and -629. In transient transfection in HepG2 cells, site-directed mutagenesis using luciferase reporter constructs containing a promoter fragment from +32 to -745 indicated that the new -690 site acts as a repressive element in reducing CETP promoter activity (-22%; p<0.05); equally, this site exerts an additive effect with the -629 site, inducing marked repression (-42%; p<0.005). In contrast, in NCTC cells which display a 16-fold lower level of Sp3, the repressive effect at the -690 site was enhanced twofold (-45%; p<0.05), whereas the -629 site exerted no effect. Co-transfection of Sp1 and/or Sp3 in SL2 insect cells lacking endogenous Sp factors demonstrated that Sp1 and Sp3 act as activators at the -690 and -37 sites, whereas Sp3 acts as a repressor at the -629 site. Taken together, our data demonstrate that Sp1 and Sp3 regulate human CETP promoter activity through three Sp1/Sp3 binding sites in a distinct manner, and that the Sp1/Sp3 ratio is a key factor in determining the relative contribution of these sites to total promoter activity.

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