DAX-1 represses the high-density lipoprotein receptor through interaction with positive regulators sterol regulatory element-binding protein-1a and steroidogenic factor-1.
The high-density lipoprotein receptor (HDL-R) mediates the selective uptake of high-density lipoprotein cholesterol in nonplacental steroidogenic tissues. We have previously demonstrated that sterol regulatory element-binding protein-1a (SREBP-1a) and steroidogenic factor-1 (SF-1) positively regulate HDL-R gene transcription. In the present study, we examined whether DAX-1 (dosage-sensitive sex adrenal hypoplasia congenital critical ... region on the X chromosome, gene-1) could influence the expression of the HDL-R gene. Cotransfection studies demonstrated that DAX-1 was able to repress SREBP-1a and SF-1-dependent activation of the HDL-R promoter. Mammalian two-hybrid assays demonstrated that DAX-1 could interact with SREBP-1a. In addition, electrophoretic mobility shift assays demonstrated that initial incubation of DAX-1 with SREBP-1a protein in the absence of DNA prevented subsequent binding of SREBP-1a to the HDL-R sterol regulatory elements in a dose-dependent manner, whereas, in the case of SF-1, DAX-1 formed a complex with SF-1 protein on the DNA. These data suggest that DAX-1 inhibits SREBP-1a- and SF-1-dependent activation of the HDL-R promoter through different mechanisms. This investigation confirms that DAX-1 has an important role in regulating steroidogenesis by interfering with SREBP-1a and SF-1 induction of a gene involved in the transport of cholesterol, thereby limiting the amount of substrate available for steroid hormone production.
Mesh Terms:
Amino Acid Motifs, Animals, Base Sequence, CCAAT-Enhancer-Binding Proteins, Carrier Proteins, Cell Line, DAX-1 Orphan Nuclear Receptor, DNA-Binding Proteins, Fushi Tarazu Transcription Factors, Gene Expression Regulation, Homeodomain Proteins, Humans, Lipoproteins, HDL, Mice, Promoter Regions, Genetic, RNA-Binding Proteins, Rats, Receptors, Cytoplasmic and Nuclear, Receptors, Lipoprotein, Receptors, Retinoic Acid, Repressor Proteins, Steroidogenic Factor 1, Sterol Regulatory Element Binding Protein 1, Transcription Factors
Amino Acid Motifs, Animals, Base Sequence, CCAAT-Enhancer-Binding Proteins, Carrier Proteins, Cell Line, DAX-1 Orphan Nuclear Receptor, DNA-Binding Proteins, Fushi Tarazu Transcription Factors, Gene Expression Regulation, Homeodomain Proteins, Humans, Lipoproteins, HDL, Mice, Promoter Regions, Genetic, RNA-Binding Proteins, Rats, Receptors, Cytoplasmic and Nuclear, Receptors, Lipoprotein, Receptors, Retinoic Acid, Repressor Proteins, Steroidogenic Factor 1, Sterol Regulatory Element Binding Protein 1, Transcription Factors
Endocrinology
Date: Dec. 01, 2001
PubMed ID: 11713202
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