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Molecular and Cellular Biology, March 2000, p. 1868-1876, Vol. 20, No. 5
Center for Cardiovascular Research,
Departments of Medicine1 and Molecular
Biology and Pharmacology,2 Washington University
School of Medicine, St. Louis, Missouri
Received 9 August 1999/Returned for modification 22 September
1999/Accepted 10 December 1999
Peroxisome proliferator-activated receptor
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
The Coactivator PGC-1 Cooperates with Peroxisome
Proliferator-Activated Receptor
in Transcriptional Control of
Nuclear Genes Encoding Mitochondrial Fatty Acid Oxidation
Enzymes
(PPAR
) plays a
key role in the transcriptional control of genes encoding mitochondrial fatty acid
-oxidation (FAO) enzymes. In this study we sought to
determine whether the recently identified PPAR gamma coactivator 1 (PGC-1) is capable of coactivating PPAR
in the transcriptional control of genes encoding FAO enzymes. Mammalian cell cotransfection experiments demonstrated that PGC-1 enhanced PPAR
-mediated
transcriptional activation of reporter plasmids containing PPAR
target elements. PGC-1 also enhanced the transactivation activity of a
PPAR
-Gal4 DNA binding domain fusion protein. Retroviral
vector-mediated expression studies performed in 3T3-L1 cells
demonstrated that PPAR
and PGC-1 cooperatively induced the
expression of PPAR
target genes and increased cellular palmitate
oxidation rates. Glutathione S-transferase "pulldown"
studies revealed that in contrast to the previously reported
ligand-independent interaction with PPAR
, PGC-1 binds PPAR
in a
ligand-influenced manner. Protein-protein interaction studies and
mammalian cell hybrid experiments demonstrated that the PGC-1-PPAR
interaction involves an LXXLL domain in PGC-1 and the PPAR
AF2
region, consistent with the observed ligand influence. Last, the PGC-1
transactivation domain was mapped to within the
NH2-terminal 120 amino acids of the PGC-1 molecule, a
region distinct from the PPAR
interacting domains. These results identify PGC-1 as a coactivator of PPAR
in the transcriptional control of mitochondrial FAO capacity, define separable PPAR
interaction and transactivation domains within the PGC-1 molecule, and
demonstrate that certain features of the PPAR
-PGC-1 interaction are
distinct from that of PPAR
-PGC-1.
*
Corresponding author. Mailing address: Center for
Cardiovascular Research, Washington University School of Medicine, 660 S. Euclid Ave., Campus Box 8086, St. Louis, MO 63110. Phone: (314) 362-8908. Fax: (314) 362-0186. E-mail:
dkelly{at}imgate.wustl.edu.
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