Aug 7, 2002

Ligand and coactivator recruitment preferences of peroxisome proliferator activated receptor alpha

The Journal of Steroid Biochemistry and Molecular Biology
Ranjan MukherjeePeter R Young

Abstract

The mechanism by which ligands of nuclear receptors show differential effects on gene transcription is not fully understood, but is believed to result in part from the preferential recruitment and/or displacement of coactivators and corepressors. We have explored the interaction of several known ligands and the nuclear receptor (peroxisome proliferator activated receptor alpha, PPARalpha) using scintillation proximity assay (SPA) and the interaction of LXXLL containing peptides derived from three coactivators (SRC-1, CBP and PGC-1) with PPARalpha in the presence of PPARalpha agonist ligands using fluorescence resonance energy transfer (FRET). The EC(50)s of the individual ligands for recruitment showed the same rank order regardless of the coactivator peptide used, with GW2331<WY14643=ciprofibrate<L165041<gemfibrozil. Similarly, for all ligands tested, the rank order of EC(50) for peptide recruitment was CBP<PGC-1<SRC-1. These data suggest that for these LXXLL coactivator peptides, the ligands do not substantially differ in their preferences. Partial agonism was observed with ciprofibrate and PGC-1 and gemfibrozil and CBP giving a lower FRET at saturation than with the other ligands. This suggests that ciprofibrate and gemfibro...Continue Reading

Mentioned in this Paper

PPARA wt Allele
Co-Repressor Proteins
Transfection
Energy Transfer
Alkalescens-Dispar Group
Transcription, Genetic
Cell Nucleus
Plasma Protein Binding Capacity
Receptors, Intracellular Membrane
NCOA1 protein, human

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