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p300 functions as a coactivator for the peroxisome proliferator-activated receptor alpha
P Dowell1, J E Ishmael, D Avram
1Program in Molecular and Cellular Biology, College of Pharmacy, Oregon State University, Corvallis, Oregon 97331, USA.
Abstract:
The integrator protein, p300, was demonstrated to interact with mouse peroxisome proliferator-activated receptor alpha in a ligand-enhanced manner. The PPARalpha-interacting domain of p300 was mapped to amino acids 39-117 which interacted strongly with PPARalpha but did not interact with retinoic acid receptor-gamma or retinoid X receptor-alpha. Amino acids within the carboxyl terminus of PPARalpha as well as residues within the hinge region were required for ligand-dependent interaction with p300. p300 enhanced the transcriptional activation properties of PPARalpha and, therefore, can be considered a bona fide coactivator for this nuclear receptor. These observations extend the group of p300-interacting proteins to include mPPARalpha and further characterize the molecular mechanisms of PPARalpha-mediated transcriptional regulation.
Insights
The p300 protein interacts with peroxisome proliferator-activated receptor alpha (PPARalpha) in a way that is enhanced by ligands. This interaction makes p300 a coactivator, enhancing PPARalpha
Area of Science:
- Molecular biology
- Cellular signaling
- Gene regulation
Background:
- p300 is a known transcriptional coactivator.
- Peroxisome proliferator-activated receptor alpha (PPARalpha) is a nuclear receptor involved in metabolic regulation.
- Understanding coactivator-nuclear receptor interactions is crucial for deciphering gene expression.
Purpose of the Study:
- To investigate the interaction between p300 and mouse PPARalpha (mPPARalpha).
- To identify the specific domains involved in the p300-mPPARalpha interaction.
- To determine the functional consequence of this interaction on transcriptional regulation.
Main Methods:
- Co-immunoprecipitation assays to demonstrate protein-protein interactions.
- Site-directed mutagenesis to map interaction domains.
- Reporter gene assays to assess transcriptional activation.
Main Results:
- p300 interacts with mPPARalpha in a ligand-dependent manner.
- The N-terminal domain of p300 (amino acids 39-117) is critical for mPPARalpha interaction.
- Specific regions in PPARalpha, including the carboxyl terminus and hinge region, are required for interaction with p300.
- p300 enhances the transcriptional activity of mPPARalpha.
Conclusions:
- p300 acts as a bona fide coactivator for mPPARalpha.
- The findings elucidate the molecular mechanisms underlying PPARalpha-mediated gene transcription.
- This study expands the known interactome of p300 to include mPPARalpha.