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J. Biol. Chem., Vol. 278, Issue 19, 17263-17268, May 9, 2003
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Expression by PGC-1*
, and
From the Department of Pathology and Laboratory Medicine, The
University of Texas Medical School at Houston, UT-Houston Health
Science Center and the Graduate School of Biomedical Sciences, The
Texas Medical Center, Houston, Texas 77030 and the
Transcriptional regulation of carnitine
palmitoyltransferase-1
Department of Pharmacology, The University of Tennessee,
Memphis, Tennessee 38163
(CPT-1
) is coordinated with contractile
gene expression through cardiac-enriched transcription factors, GATA4
and SRF. Metabolic modulation of CPT-1
promoter activity
has been described with the stimulation of gene expression by oleate
that is mediated through the peroxisome proliferator-activated receptor
(PPAR) pathway. The coactivator, peroxisomal proliferator-activated
receptor
coactivator (PGC-1), enhances gene expression through
interactions with nuclear hormone receptors and the myocyte enhancer
factor 2 (MEF2) family. PGC-1 and MEF2A synergistically activate
CPT-1
promoter activity. This stimulation is enhanced by
mutation of the E-box sequences that flank the MEF2A binding site.
These elements bind the upstream stimulatory factors (USF1 and USF2),
which activate transcription in CV-1 fibroblasts. However,
overexpression of the USF proteins in myocytes depresses CPT-1
activity and significantly reduces MEF2A and PGC-1 synergy.
Co-immunoprecipitation studies demonstrate that PGC-1 and USF2 proteins
can physically interact. Our studies demonstrate that PGC-1 stimulates
CPT-1
gene expression through MEF2A. USF proteins
have a novel role in repressing the expression of the
CPT-1
gene and modulating the induction by the
coactivator, PGC
1.
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