Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.3.99.3 (acyl-CoA dehydrogenase)
 1,425 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

Recent studies indicate that retinoid-mediated pathways play a pivotal role in cardiac morphogenesis and function. To identify proteins that serve as interacting partners of the retinoid X receptor alpha (RXRalpha) in heart, DNA-protein binding studies were performed with an RXR-responsive element (NRRE-1) derived from the medium chain acyl-CoA dehydrogenase gene promoter and nuclear protein extracts prepared from adult rat heart. NRRE-1 is a pleiotropic RXR-responsive element comprised of three potential recognition sites for class II members of the nuclear receptor superfamily. Gel mobility shift assays performed with an NRRE-1 probe in the absence or presence of bacterially overproduced RXRalpha and nuclear protein extracts prepared from adult rat heart, liver, or brain identified a cardiac-specific, RXR-dependent DNA-protein interaction. The NRRE-1-RXR.cardiac-enriched RXR-interacting protein (CERIP) complex exhibited a distinct mobility compared with NRRE-1-RXR.peroxisome proliferator-activated receptor, NRRE-1-RXR.retinoic acid receptor, or NRRE-1-RXR.thyroid receptor complexes. Mutational analysis demonstrated that two of the three potential binding half-sites of NRRE-1 (an everted repeat separated by an 8-base pair spacer) are required for the NRRE-1-RXR. CERIP interaction. Gel mobility shift assays demonstrated that CERIP interacted with RXRalpha and RXRgamma but not with RXRbeta, indicating a receptor subtypespecific binding preference and suggesting an RXR AB region-dependent interaction. The RXR.CERIP complex did not form on NRRE-1 when a mutant GST-RXRalpha fusion protein lacking the NH(2)-terminal AB region (but containing the receptor dimerization domain) of RXRalpha was added in place of the full-length RXRalpha, confirming a role for the AB region in the RXR. CERIP interaction. DNA-protein cross-linking studies demonstrated that CERIP is a DNA-binding protein of approximately 110 kDa. These results provide evidence for the existence of a cardiac-enriched DNA-binding protein that interacts with RXRalpha via the AB region and suggest a mechanism whereby cardiac retinoid signaling is controlled in an RXR subtype-specific manner.
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PMID:Evidence for a novel cardiac-enriched retinoid X receptor partner. 1046 3