Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.3.1.28 (chloramphenicol acetyltransferase)
 5,100 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To study the mechanisms involved in regulation of nuclear genes encoding mitochondrial enzymes in oxidative energy pathways, the promoter region of the medium-chain acyl-CoA dehydrogenase (MCAD) gene was analyzed. A series of hexamer sequences known to bind and confer responsiveness to a subset of members of the nuclear receptor superfamily of transcription factors was identified. Cotransfection of an MCAD promoter-chloramphenicol acetyltransferase (CAT) reporter plasmid with retinoic acid receptor (RAR)alpha, beta, or retinoid X receptor alpha (RXR alpha) resulted in 10-15-fold transcriptional activation in response to retinoic acid. The retinoic acid-induced activation was 3-4-fold higher with RXR alpha than with either RAR alpha or RAR beta. Deletional analysis confirmed that a region between -341 and -308 base pairs upstream of the MCAD gene cap site conferred the RA-responsive transcriptional activation to homologous and heterologous promoters. Gel mobility shift assays demonstrated that the MCAD RARE interacted directly with overexpressed receptors. Mutational analysis of the RARE delineated three hexamer binding sequences with unique orientation and spacing compared to other reported retinoid responsive elements. These results indicate that the MCAD gene promoter region contains a novel regulatory element that interacts with members of the retinoid receptor family, with preferential activation by RXR alpha. This element likely plays a role in the transcriptional regulation of this gene and perhaps others involved in oxidative energy metabolism.
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PMID:Identification of a novel retinoid-responsive element in the promoter region of the medium chain acyl-coenzyme A dehydrogenase gene. 132 96

During cardiac hypertrophy, the chief myocardial energy source switches from fatty acid beta-oxidation (FAO) to glycolysis-a reversion to fetal metabolism. The expression of genes encoding myocardial FAO enzymes was delineated in a murine ventricular pressure overload preparation to characterize the molecular regulatory events involved in the alteration of energy substrate utilization during cardiac hypertrophy. Expression of genes involved in the thioesterification, mitochondrial import, and beta-oxidation of fatty acids was coordinately down-regulated after 7 days of right ventricular (RV) pressure overload. Results of RV pressure overload studies in mice transgenic for the promoter region of the gene encoding human medium-chain acyl-CoA dehydrogenase (MCAD, which catalyzes a rate-limiting step in the FAO cycle) fused to a chloramphenicol acetyltransferase reporter confirmed that repression of MCAD gene expression in the hypertrophied ventricle occurred at the transcriptional level. Electrophoretic mobility-shift assays performed with MCAD promoter fragments and nuclear protein extracts prepared from hypertrophied and control RV identified pressure overload-induced protein/DNA interactions at a regulatory unit shown previously to confer control of MCAD gene transcription during cardiac development. Antibody "supershift" studies demonstrated that members of the Sp (Sp1, Sp3) and nuclear hormone receptor [chicken ovalbumin upstream promoter transcription factor (COUP-TF)/erbA-related protein 3] families interact with the pressure overload-responsive unit. Cardiomyocyte transfection studies confirmed that COUP-TF repressed the transcriptional activity of the MCAD promoter. The DNA binding activities and nuclear expression of Sp1/3 and COUP-TF in normal fetal mouse heart were similar to those in the hypertrophied adult heart. These results identify a transcriptional regulatory mechanism involved in the reinduction of a fetal metabolic program during pressure overload-induced cardiac hypertrophy.
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PMID:A role for Sp and nuclear receptor transcription factors in a cardiac hypertrophic growth program. 917 36