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Characterization of a cholesterol response element (CRE) in the promoter of the cholesteryl ester transfer protein gene: functional role of the transcription factors SREBP-1a, -2, and YY1.

Publication ,  Journal Article
Gauthier, B; Robb, M; Gaudet, F; Ginsburg, GS; McPherson, R
Published in: J Lipid Res
July 1999

Cholesteryl ester transfer protein (CETP) is expressed in human adipocytes, where it acts to promote selective uptake of HDL-CE (Benoist, F., M. McDonnell, P. Lau, R. Milne, and R. McPherson. 1997. J. Biol. Chem. 272: 23572;-23577). In contrast to other major sterol-responsive genes such as 3-hydroxy-3-methylglutaryl coenzyme A reductase CETP expression is up-regulated rather than down-regulated in response to cholesterol. To define elements involved in cholesterol-mediated up-regulation of CETP gene expression, deletion derivatives of the CETP promoter were cloned into a luciferase reporter construct and transfected into the human liposarcoma cell line SW872, cultured in the presence or absence of lipoproteins. A fragment associated with a positive cholesterol response was identified between nucleotides -361 and -138 (relative to the initiation site of transcription) of the promoter. This region contains a tandem repeat of a sequence known to mediate sterol dependent regulation of the hamster HMG-CoA reductase gene. We have putatively denoted this region, the cholesterol response element (CRE). Using gel mobility shift assays we demonstrate that both YY1 and SREBP-1 interact with the CRE of CETP. Furthermore, in transient co-transfection experiments, both YY1 and SREBP-1a were found to trans-activate, in a dose-dependent manner, the luciferase activity of constructs harboring the CRE. We also demonstrate that SREBP-2, is able to trans-activate a luciferase construct harboring the CRE although much less effectively as compared to SREBP-1. Finally, functional analysis of the CRE confirms its regulatory role in modulating CETP gene expression through its interaction with YY1 and SREBP-1a.

Duke Scholars

Published In

J Lipid Res

ISSN

0022-2275

Publication Date

July 1999

Volume

40

Issue

7

Start / End Page

1284 / 1293

Location

United States

Related Subject Headings

  • Zinc Fingers
  • YY1 Transcription Factor
  • Tumor Cells, Cultured
  • Transfection
  • Transcription, Genetic
  • Transcription Factors
  • Sterol Regulatory Element Binding Protein 2
  • Sterol Regulatory Element Binding Protein 1
  • Sequence Analysis, DNA
  • RNA, Messenger
 

Published In

J Lipid Res

ISSN

0022-2275

Publication Date

July 1999

Volume

40

Issue

7

Start / End Page

1284 / 1293

Location

United States

Related Subject Headings

  • Zinc Fingers
  • YY1 Transcription Factor
  • Tumor Cells, Cultured
  • Transfection
  • Transcription, Genetic
  • Transcription Factors
  • Sterol Regulatory Element Binding Protein 2
  • Sterol Regulatory Element Binding Protein 1
  • Sequence Analysis, DNA
  • RNA, Messenger