Yin yang 1 protein negatively regulates high-density lipoprotein receptor gene transcription by disrupting binding of sterol regulatory element binding protein to the sterol regulatory element.
Because the high-density lipoprotein receptor (HDL-R) is a key element in cholesterol homeostasis and a potential therapeutic target for hypercholesterolemic drugs, an understanding of HDL-R regulation is essential. The sterol regulatory element (SRE) binding protein-1a (SREBP-1a) was shown to positively regulate HDL-R gene expression through two SREs. SREBP-1a requires the presence of a coactivator like simian-virus-40-protein-1 (Sp1) to promote maximum activation of the HDL-R promoter. Negative regulatory factors are also known to play a role in cholesterol homeostasis, and the ubiquitous Yin Yang-1 zinc finger transcription factor (YY1) has been shown to repress several sterol-responsive gene promoters. A search of the rat HDL-R promoter revealed two putative YY1 binding sites (distal, -1329 to -1321; proximal, -1211 to -1203). Upon removal of both YY1 binding sites, YY1 was unable to repress HDL-R activation under basal (unstimulated) promoter conditions. However, YY1 was still an efficient transcriptional repressor for SREBP-1a-induced activation. YY1 was able to attenuate the transcriptional synergy caused by the combined actions of SREBP-1a and Sp1. Two-hybrid studies confirmed that YY1 bound with high affinity to SREBP-1a, and mobility shift assays demonstrated that YY1 could disrupt SREBP-1a binding to both SREs. The molecular consequence of YY1 intervention seems to override any positive interactions between Sp-1 and SREBP-1a and results in the disruption of SREBP-1a binding to the SREs in the HDL-R promoter.
Shea-Eaton
W
W
Departments of Obstetrics and Gynecology and Biochemistry and Molecular Biology, University of South Florida, College of Medicine, Tampa, Florida 33606, USA.
Lopez
D
D
McLean
M P
MP
D000818:Animals; D001665:Binding Sites; D022762:CCAAT-Enhancer-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D050981:Erythroid-Specific DNA-Binding Factors; D005786:Gene Expression Regulation / Q000502:physiology*; D017930:Genes, Reporter; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D008075:Lipoproteins, HDL; D008156:Luciferases / Q000235:genetics; D051379:Mice; D011401:Promoter Regions, Genetic; D016601:RNA-Binding Proteins; D018110:Receptors, Lipoprotein / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid; D012097:Repressor Proteins / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology*; D014162:Transfection; D050986:YY1 Transcription Factor
D022762:CCAAT-Enhancer-Binding Proteins; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D008075:Lipoproteins, HDL; D016601:RNA-Binding Proteins; D018110:Receptors, Lipoprotein; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D012097:Repressor Proteins; C497387:SREBF1 protein, human; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D050986:YY1 Transcription Factor; C494698:YY1 protein, human; C494699:Yy1 protein, mouse; C031616:high density lipoprotein receptors; C075197:high density lipoprotein binding protein; D008156:Luciferases; D005982:Glutathione Transferase