TY - JOUR

T1 - Nuclear receptor corepressor-dependent repression of peroxisomeproliferator-activated receptor d-mediated transactivation

AU - Krogsdam, Anne-M

AU - Nielsen, Curt A F

AU - Neve, Søren

AU - Holst, Dorte

AU - Helledie, Torben

AU - Thomsen, Bo

AU - Bendixen, Christian

AU - Mandrup, Susanne

AU - Kristiansen, Karsten

N1 - Keywords: Animals; Cell Line; DNA-Binding Proteins; Dimerization; Dose-Response Relationship, Drug; Glutathione Transferase; Humans; Ligands; Mice; Nuclear Proteins; Protein Binding; Protein Biosynthesis; Protein Structure, Tertiary; Receptors, Cytoplasmic and Nuclear; Recombinant Fusion Proteins; Repressor Proteins; Transcription Factors; Transcription, Genetic; Transcriptional Activation; Transfection; Two-Hybrid System Techniques

PY - 2002

Y1 - 2002

N2 - 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.

AB - 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.

M3 - Journal article

C2 - 11903058

VL - 363

SP - 157

EP - 165

JO - Biochemical Journal

JF - Biochemical Journal

SN - 0264-6021

IS - Pt 1

ER -