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.
Lopez
D
D
Department of Obstetrics and Gynecology, University of South Florida, Tampa, Florida 33606, USA.
Shea-Eaton
W
W
Sanchez
M D
MD
McLean
M P
MP
D020816:Amino Acid Motifs / Q000502:physiology; D000818:Animals; D001483:Base Sequence / Q000235:genetics; D022762:CCAAT-Enhancer-Binding Proteins / Q000502:physiology*; D002352:Carrier Proteins; D002460:Cell Line; D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins / Q000502:physiology*; D051717:Fushi Tarazu Transcription Factors; D005786:Gene Expression Regulation / Q000502:physiology; D018398:Homeodomain Proteins; D006801:Humans; D008075:Lipoproteins, HDL; D051379:Mice; D011401:Promoter Regions, Genetic / Q000502:physiology; D016601:RNA-Binding Proteins; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear; D018110:Receptors, Lipoprotein / Q000037:antagonists & inhibitors* / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000502:physiology*; D012097:Repressor Proteins; D054339:Steroidogenic Factor 1; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors / Q000502:physiology*
D022762:CCAAT-Enhancer-Binding Proteins; D002352:Carrier Proteins; D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins; D051717:Fushi Tarazu Transcription Factors; D018398:Homeodomain Proteins; D008075:Lipoproteins, HDL; C539965:NR0B1 protein, human; C515057:NR5A1 protein, human; C539966:Nr0b1 protein, mouse; C539967:Nr0b1 protein, rat; D016601:RNA-Binding Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D018110:Receptors, Lipoprotein; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; C497387:SREBF1 protein, human; C497388:Srebf1 protein, mouse; C497389:Srebf1 protein, rat; D054339:Steroidogenic Factor 1; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; C031616:high density lipoprotein receptors; C515058:steroidogenic factor 1, mouse; C515060:steroidogenic factor 1, rat; C075197:high density lipoprotein binding protein