Upstream stimulatory factor represses the induction of carnitine palmitoyltransferase-Ibeta expression by PGC-1.
Transcriptional regulation of carnitine palmitoyltransferase-1beta (CPT-1beta) is coordinated with contractile gene expression through cardiac-enriched transcription factors, GATA4 and SRF. Metabolic modulation of CPT-1beta 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 gamma 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-1beta 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-1beta 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-1beta gene expression through MEF2A. USF proteins have a novel role in repressing the expression of the CPT-1beta gene and modulating the induction by the coactivator, PGC-1.
Moore
Meredith L
ML
Department of Pathology and Laboratory Medicine, The University of Texas Medical School at Houston, UT-Houston Health Science Center, The Texas Medical Center, Houston, Texas 77030, USA.
Park
Edwards A
EA
McMillin
Jeanie B
JB
D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004790:Enzyme Induction / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; D011485:Protein Binding; D051381:Rats; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D051720:Upstream Stimulatory Factors
D004268:DNA-Binding Proteins; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; D014157:Transcription Factors; D051720:Upstream Stimulatory Factors; C497182:Usf1 protein, rat; C497187:Usf2 protein, rat; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; D002334:Carnitine O-Palmitoyltransferase