Nuclear receptor corepressor-dependent repression of peroxisome-proliferator-activated receptor delta-mediated transactivation

The nuclear receptor corepressor (NCoR) was isolated as a peroxisome-proliferator-activated receptor (PPAR) delta interacting protein using the yeast two-hybrid system. NCoR interacted strongly with the ligand-binding domain of PPAR delta, whereas interactions with the ligand-binding domains of PPAR...

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Vydané v:Biochemical journal Ročník 363; číslo Pt 1; s. 157
Hlavní autori: Krogsdam, Anne-M, Nielsen, Curt A F, Neve, Søren, Holst, Dorte, Helledie, Torben, Thomsen, Bo, Bendixen, Christian, Mandrup, Susanne, Kristiansen, Karsten
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: England 01.04.2002
Predmet:
Animals
Cell Line
Dimerization
DNA-Binding Proteins - metabolism
Dose-Response Relationship, Drug
Glutathione Transferase - metabolism
Humans
Ligands
Mice
Nuclear Proteins - metabolism
Nuclear Receptor Co-Repressor 1
Nuclear Receptor Co-Repressor 2
Protein Binding
Protein Biosynthesis
Protein Structure, Tertiary
Receptors, Cytoplasmic and Nuclear - chemistry
Receptors, Cytoplasmic and Nuclear - metabolism
Recombinant Fusion Proteins - metabolism
Repressor Proteins - metabolism
Transcription Factors - chemistry
Transcription Factors - metabolism
Transcription, Genetic
Transcriptional Activation
Transfection
Two-Hybrid System Techniques
ISSN:0264-6021
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Shrnutí:The nuclear receptor corepressor (NCoR) was isolated as a peroxisome-proliferator-activated receptor (PPAR) delta interacting protein using the yeast two-hybrid system. NCoR interacted strongly with the ligand-binding domain of PPAR delta, whereas interactions with the ligand-binding domains of PPAR gamma and PPAR alpha were significantly weaker. PPAR-NCoR interactions were antagonized by ligands in the two-hybrid system, but were ligand-insensitive in in vitro pull-down assays. Interaction between PPAR delta and NCoR was unaffected by coexpression of retinoid X receptor (RXR) alpha. The PPAR delta-RXR alpha heterodimer bound to an acyl-CoA oxidase (ACO)-type peroxisome-proliferator response element recruited a glutathione S-transferase-NCoR fusion protein in a ligand-independent manner. Contrasting with most other nuclear receptors, PPAR delta was found to interact equally well with interaction domains I and II of NCoR. In transient transfection experiments, NCoR and the related silencing mediator for retinoid and thyroid hormone receptor (SMRT) were shown to exert a marked dose-dependent repression of ligand-induced PPAR delta-mediated transactivation; in addition, transactivation induced by the cAMP-elevating agent forskolin was efficiently reduced to basal levels by NCoR as well as SMRT coexpression. Our results suggest that the transactivation potential of liganded PPAR delta can be fine-tuned by interaction with NCoR and SMRT in a manner determined by the expression levels of corepressors and coactivators.
Bibliografia:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0264-6021
DOI:10.1042/0264-6021:3630157