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Molecular and Cellular Biology, August 2009, p. 4091-4102, Vol. 29, No. 15
0270-7306/09/$08.00+0 doi:10.1128/MCB.01669-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Bcl3 Interacts Cooperatively with Peroxisome Proliferator-Activated Receptor Gamma (PPAR
) Coactivator 1
To Coactivate Nuclear Receptors Estrogen-Related Receptor and PPAR 
,
John Yang,1,2
R. Sanders Williams,5 and
Daniel P. Kelly1,2,3,4*
Center for Cardiovascular Research,1 Departments of Medicine,2 Developmental Biology,3 Pediatrics, Washington University School of Medicine, St. Louis, Missouri,4 Department of Medicine, Duke University School of Medicine, Durham, North Carolina5
Received 28 October 2008/ Returned for modification 26 November 2008/ Accepted 12 May 2009
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 (PPAR
) coactivator 1
(PGC-1). A yeast two-hybrid screen led to the identification of the cytokine-stimulated transcriptional regulator, Bcl3, as an ERR coactivator. Bcl3 was shown to synergize with PGC-1 to coactivate ERR. Chromatin immunoprecipitation studies demonstrated that ERR, PGC-1, and Bcl3 form a complex on an ERR-responsive element within the pyruvate dehydrogenase kinase 4 gene promoter in cardiac myocytes. Mapping studies demonstrated that Bc13 interacts with PGC-1 and ERR, 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-1, ERR, and a second nuclear receptor, PPAR. Consistent with the gene expression profiling results, Bcl3 was shown to synergistically coactivate PPAR with PGC-1 in a manner similar to ERR. We propose that the cooperativity between Bcl3 and PGC-1 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.
* Corresponding author. Present address: Burnham Institute for Medical Research, 6400 Sanger Rd., Orlando, FL 32827. Phone: (407) 745-2069. Fax: (407) 745-2001. E-mail: dkelly{at}burnham.org
Published ahead of print on 18 May 2009.
Supplemental material for this article may be found at http://mcb.asm.org/.
Molecular and Cellular Biology, August 2009, p. 4091-4102, Vol. 29, No. 15
0270-7306/09/$08.00+0 doi:10.1128/MCB.01669-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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