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)

We previously identified a complex regulatory element in the medium-chain acyl coenzyme A dehydrogenase gene promoter that confers transcriptional regulation by the retinoid receptors RAR and RXR and the orphan nuclear receptor HNF-4. In this study we demonstrate a trans-repressing regulatory function for the orphan receptor COUP-TF at this same nuclear receptor response element (NRRE-1). The transcriptional regulatory properties and receptor binding sequences of each nuclear receptor response element within NRRE-1 are also characterized. NRRE-1 consists of four potential nuclear hormone receptor hexamer binding sites, arranged as [<--1-(n)s-2-->-3-->(n)4<--4], three of which are used in alternative pairwise binding by COUP-TF and HNF-4 homodimers and by RAR-RXR heterodimers, as demonstrated by mobility shift assays and methylation interference analysis. Binding and transactivation studies with mutant NRRE-1 elements confirmed the existence of distinct retinoid, COUP-TF, and HNF-4 response elements that define novel receptor binding motifs: COUP-TF homodimers bound sites 1 and 3 (two hexamer repeat sequences arranged as an everted imperfect repeat separated by 14 bp or ER14), RAR-RXR heterodimers bound sites 1 and 2 (ER8), and HNF-4 homodimers bound sites 2 and 3 (imperfect DR0). Mixing cotransfection experiments demonstrated that the nuclear receptor dimers compete at NRRE-1 to modulate constitutive and ligand-mediated transcriptional activity. These data suggest a mechanism for the transcriptional modulation of genes encoding enzymes involved in cellular metabolism.
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PMID:A pleiotropic element in the medium-chain acyl coenzyme A dehydrogenase gene promoter mediates transcriptional regulation by multiple nuclear receptor transcription factors and defines novel receptor-DNA binding motifs. 800 45

We have recently identified a complex transcriptional regulatory element in the medium chain acyl-CoA dehydrogenase (MCAD) gene promoter region that confers response to retinoids through interaction with receptors for all-trans-retinoic acid (RARs) and 9-cis-retinoic acid (RXRs) (Raisher, B. D., Gulick, T., Zhang, Z., Strauss, A. W., Moore, D. D., and Kelly, D. P. (1992) J. Biol. Chem. 267, 20264-20269). We examined the interaction of this element (RAREMCAD) with hepatocyte nuclear factor-4 (HNF-4), an orphan receptor with a tissue expression pattern similar to that of MCAD. Electrophoretic mobility shift assays and cotransfection experiments showed that HNF-4 binds with high affinity to RAREMCAD to activate transcription by an RXR-independent mechanism. Mutational analysis revealed that the MCAD HNF-4 response element consists of an imperfect direct repeat homologous to the consensus sequence for binding to the thyroid receptor/RAR/RXR subgroup of receptors and that distinct sequence requirements dictate HNF-4 binding and transactivation. Mobility shift assays with anti-HNF-4 antiserum demonstrated that the MCAD HNF-4 response element binds endogenous rat liver HNF-4 supporting its role in the regulation of MCAD gene expression in vivo. Thus, HNF-4 activates MCAD gene transcription via a complex regulatory element, the architecture of which carries important implications for the structure of HNF-4 response elements in general.
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PMID:Hepatocyte nuclear factor-4 activates medium chain acyl-CoA dehydrogenase gene transcription by interacting with a complex regulatory element. 831 50