Bcl3 interacts cooperatively with peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator 1alpha to coactivate nuclear receptors estrogen-related receptor alpha and PPARalpha.
Estrogen-related receptors (ERRs) play critical roles in regulation of cellular energy metabolism in response to inducible coactivators such as peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator 1alpha (PGC-1alpha). A yeast two-hybrid screen led to the identification of the cytokine-stimulated transcriptional regulator, Bcl3, as an ERRalpha coactivator. Bcl3 was shown to synergize with PGC-1alpha to coactivate ERRalpha. Chromatin immunoprecipitation studies demonstrated that ERRalpha, PGC-1alpha, and Bcl3 form a complex on an ERRalpha-responsive element within the pyruvate dehydrogenase kinase 4 gene promoter in cardiac myocytes. Mapping studies demonstrated that Bc13 interacts with PGC-1alpha and ERRalpha, allowing for interaction with both proteins. Transcriptional profiling demonstrated that Bcl3 activates genes involved in diverse pathways including a subset involved in cellular energy metabolism known to be regulated by PGC-1alpha, ERRalpha, and a second nuclear receptor, PPARalpha. Consistent with the gene expression profiling results, Bcl3 was shown to synergistically coactivate PPARalpha with PGC-1alpha in a manner similar to ERRalpha. We propose that the cooperativity between Bcl3 and PGC-1alpha may serve as a point of convergence on nuclear receptor targets to direct programs orchestrating inflammatory and energy metabolism responses in heart and other tissues.
Yang
John
J
Burnham Institute for Medical Research, 6400 Sanger Road, Orlando, FL 32827, USA.
Williams
R Sanders
RS
Kelly
Daniel P
DP
D000818:Animals; D000831:Animals, Newborn; D000081242:B-Cell Lymphoma 3 Protein; D015153:Blotting, Western; D019556:COS Cells; D002460:Cell Line; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D047369:Chromatin Immunoprecipitation; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D020798:Two-Hybrid System Techniques
D000081242:B-Cell Lymphoma 3 Protein; C000631344:BCL3 protein, human; D047628:Estrogen Receptor alpha; D006360:Heat-Shock Proteins; D047493:PPAR alpha; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D008156:Luciferases