Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P19793 (retinoid X receptor alpha)
 391 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mouse peroxisome proliferator-activated receptor alpha (mP-PAR alpha) can activate transcription from the CYP4A6 promoter in transient cotransfection experiments in the absence (intrinsic transactivation) or presence of added peroxisome proliferator. However, mPPAR alpha-G, in which glycine is substituted for Glu282, exhibits very low intrinsic transactivation and responds fully to added peroxisome proliferators. The two receptors, when expressed in COS-1 cells, are nuclear in localization, are expressed at similar levels, have similar stability, and bind DNA in vitro with similar efficiency. The phenotypic difference in intrinsic transactivation is not altered by overexpression of the human retinoid X receptor alpha. The mPPAR alpha-G mutant receptor displays a higher EC50 for pirinixic acid and for 5,8,11,14-eicosatetraynoic acid than the wild-type PPAR alpha. This difference in the apparent EC50 value is independent of the cell lines used and indicates that the Glu282 to glycine substitution alters the response of mPPAR alpha to peroxisome proliferators. The EC50 values obtained for each receptor with the CYP4A6 reporter construct are lower than those for a reporter derived from the acyl-CoA oxidase gene. In general, an inverse relation is evident between the apparent EC50 values and the extent of intrinsic transactivation observed. The difference in intrinsic transactivation may reflect the presence of an endogenous activator at a concentration that is not sufficient to activate the mPPAR alpha-G but that is sufficient to effect the intrinsic transactivation seen for the wild-type mPPAR alpha.
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PMID:A single amino acid change in the mouse peroxisome proliferator-activated receptor alpha alters transcriptional responses to peroxisome proliferators. 756 38

The gene encoding cytochrome P-450 4A6 (CYP4A6) is transcriptionally activated by peroxisome proliferators. This response is dependent on a strong enhancer element (Z) and weaker elements (X and -27). The peroxisome proliferator response is mediated by the binding of heterodimers containing the peroxisome proliferator-activated receptor alpha (PPAR alpha) and the retinoid X receptor alpha (RXR alpha) to these elements. These peroxisome proliferator response elements (PPREs) contain imperfect direct repeats of the nuclear receptor consensus recognition sequence with a spacing of one nucleotide (DR1) (AGGTCA N AGGTCA). This DR1 motif is seen in the binding sites for other nuclear receptor complexes, such as ARP-1, HNF-4, and RXR alpha homodimers. Mutational analysis of the Z element reveals that the DR1 motif is required for the transcriptional activation of the CYP4A6 gene by peroxisome proliferators; however, deletion of sequences immediately upstream of this motif also abolishes this response. Oligonucleotides corresponding to truncated and mutated Z elements were assayed by gel retardation for binding to RXR alpha, PPAR alpha, and ARP-1. Deletions or mutations within six nucleotides 5' of the DR1 motif dramatically diminish PPAR alpha.RXR alpha binding without reducing the binding of either RXR alpha or ARP-1 homodimers, whereas mutation or deletion of the core DR1 sequences abolishes the binding of PPAR alpha.RXR alpha heterodimers and of RXR alpha or ARP-1 homodimers. Thus, the DR1 motif in the Z element is not sufficient to constitute a PPRE. Moreover, the binding of PPAR alpha.RXR alpha to the Z element requires sequences immediately 5' of the DR1. These sequences are conserved in natural PPREs and promote binding of PPAR alpha.RXR alpha heterodimers in preference to potential competitors such as ARP-1 and RXR alpha.
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PMID:Novel sequence determinants in peroxisome proliferator signaling. 760 74

P450 4A6 is highly induced by peroxisome proliferators in vivo. Gene transfer experiments indicate that this induction can be mediated by the mouse peroxisome proliferator-activated receptor alpha (PPAR alpha) and that it is dependent on upstream enhancer elements in the CYP4A6 gene. However, as has been seen for other peroxisome proliferator response elements (PPREs), PPAR alpha does not bind directly to a previously characterized PPRE of the CYP4A6 gene in the absence of additional proteins such as the retinoid X receptor alpha (RXR alpha). When PPAR alpha and RXR alpha are coexpressed, the overall transcription of the CYP4A6 reporter is increased, and a synergistic response to both retinoids and peroxisome proliferators is evident that is dependent on the presence of both receptors. In addition, a cryptic response element is unmasked in constructs lacking the upstream enhancers. DNase I protection assays indicate that when present together, but not singly, PPAR alpha and RXR alpha bind to a site located within 29 base pairs upstream of the CYP4A6 transcription start site. This region contains a sequence similar to that found in the apolipoprotein CIII gene that has been shown to bind RXR alpha and the orphan nuclear receptor, ARP-1. The corresponding sequence in the CYP4A6 gene also binds ARP-1. A similar sequence found in the promoter region of the rat CYP4A1 gene does not, however, bind either PPAR alpha/RXR alpha or ARP-1. Transfection of increasing amounts of the ARP-1 expression vector blocks the PPAR alpha/RXR alpha-mediated induction of transcription from the CYP4A6 promoter. Mutations that prevent the binding of either PPAR alpha/RXR alpha or ARP-1 to a double-stranded oligonucleotide corresponding to the proximal enhancer eliminate the peroxisome proliferator-induced transcriptional response observed for the promoter construct in the presence of PPAR alpha/RXR alpha, but these mutations do not eliminate the response seen when the upstream enhancers are present. These results indicate that the PPREs of the CYP4A6 gene are recognized by multiple members of the nuclear receptor family that are likely to contribute to the regulation of CYP4A6 expression in both an agonistic (RXR alpha) and an antagonistic (ARP-1) manner.
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PMID:Interaction of the peroxisome proliferator-activated receptor alpha with the retinoid X receptor alpha unmasks a cryptic peroxisome proliferator response element that overlaps an ARP-1-binding site in the CYP4A6 promoter. 802 69

We have identified cis-acting elements and trans-acting factors that regulate constitutive expression of the human antithrombin gene. The activity of the sequences flanking the first exon of the gene was investigated using a luciferase-based reporter assay in transiently transfected HepG2, COS1, BSC40, and HeLa cells. Deletion analysis allowed the mapping of two elements able to promote antithrombin gene transcription in HepG2 and COS1 cells. The first element is located upstream of the first exon (-150/+68 nucleotides). The second element is in the first intervening sequence (+300/+700 nucleotides) and functions in an orientation opposite to that of the first. Footprint analysis showed three protected areas in the 5' upstream element at -92/-68 (element A), -14/+37 (element B), and -126/-100 nucleotides (element C). These elements acted as enhancers in luciferase reporter assays. Gel retardation analysis demonstrated that two liver-enriched transcription factors, hepatocyte nuclear factor 4 (HNF4) and CCAAT enhancer-binding protein (C/EBPa), bound to the 5' upstream element. HNF4 bound to elements A and C, whereas C/EBPa bound to element B. Element A also interacted with the ubiquitous nuclear hormone receptors chicken ovalbumin upstream promoter transcription factor 1 (COUP-TF1), thyroid hormone receptor alpha (TRalpha), peroxisome proliferator-activated receptor alpha(PPARalpha), and retinoid X receptor alpha (RXRalpha). In HepG2 and BSC40 cells, HNF4, C/EBPalpha, and RXRalpha activated luciferase expression from a reporter construct containing the 5'-upstream minimal antithrombin gene promoter, while COUP-TF1, TRalpha, and HNF3 (alpha or beta) repressed such expression. Our results show that constitutive expression of the human antithrombin gene depends in part upon the interplay of these transcription factors and suggest that signaling pathways regulated by these factors can modulate antithrombin gene transcription.
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PMID:Regions flanking exon 1 regulate constitutive expression of the human antithrombin gene. 891 Jun 19

We have investigated the basis of the lack of activity of a natural variant human peroxisome proliferator-activated receptor alpha, hPPARalpha6/29. A subcloning approach was used to change the four variant amino acids in the hPPARalpha6/29 sequence, individually and in combination, to those found in an active human PPARalpha. Individual amino acid "back mutations" were unable to confer on hPPARalpha6/29 the ability to be activated by peroxisome proliferators in a transient transfection assay. Although hPPARalpha6/29 was able to bind specifically to DNA in the presence of the retinoid X receptor alpha (RXRalpha), the complete restoration of receptor transcriptional activity required two separate back mutations of the hPPARalpha6/29 sequence, namely amino acid 123 in the DNA binding domain, and amino acid 444 close to the C-terminus. This suggests that sequences in the PPARalpha DNA binding domain influence other receptor functions besides DNA binding.
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PMID:Amino acid residues in both the DNA-binding and ligand-binding domains influence transcriptional activity of the human peroxisome proliferator-activated receptor alpha. 934 63

Both the mRNA and protein of cellular retinol-binding protein, type two (CRBP(II)) are induced in rat intestine by high fat (corn oil) diet (Biochim. Biophys. Acta 1200, 34-40, 1994) as well as by dietary unsaturated long-chain fatty acids (J. Nutr. 125, 2039-2044, 1995). To gain an insight into the mechanism for this induction, we investigated whether CRBP(II) gene was activated by exposure of the human intestinal cell line, Caco-2 to a peroxisome proliferator (clofibric acid) and/or 9-cis retinoic acid. Northern blot hybridization revealed that Caco-2 cells endogenously expressed the mRNAs of peroxisome proliferator-activated receptor alpha (PPARalpha) and retinoid X receptor alpha (RXRalpha). The expression of the genes encoding CRBP(II), PPARalpha, and RXRalpha increased progressively during differentiation of Caco-2 cells. The cells exposed to 100 microM clofibric acid exhibited 70% greater CRBP(II) mRNA and the exposure of the cells to 100 microM clofibric acid in combination with 100 microM 9-cis retinoic acid exhibited 130% greater CRBP(II) mRNA level, indicating that the effect of the combination of them was additive. Neither PPARalpha mRNA nor RXRalpha mRNA level was enhanced by clofibric acid. In conclusion, our data suggested that the CRBP(II) gene expression may be enhanced by an activation of PPARalpha-RXRalpha heterodimer through some putative metabolite(s) formed via fatty acid-related metabolic pathway in the clofibrc acid-treated cells.
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PMID:Peroxisome proliferator enhances gene expression of cellular retinol-binding protein, type II in Caco-2 cells. 949 8

To explore the gene regulatory mechanisms involved in the metabolic control of cardiac fatty acid oxidative flux, the expression of muscle-type carnitine palmitoyltransferase I (M-CPT I) was characterized in primary cardiac myocytes in culture following exposure to the long-chain mono-unsaturated fatty acid, oleate. Oleate induced steady-state levels of M-CPT I mRNA 4.5-fold. The transcription of a plasmid construct containing the human M-CPT I gene promoter region fused to a luciferase gene reporter transfected into cardiac myocytes, was induced over 20-fold by long-chain fatty acid in a concentration-dependent and fatty acyl-chain length-specific manner. The M-CPT I gene promoter fatty acid response element (FARE-1) was localized to a hexameric repeat sequence located between 775 and 763 base pairs upstream of the initiator codon. Cotransfection experiments with expression vectors for the peroxisome proliferator-activated receptor alpha (PPARalpha) demonstrated that FARE-1 is a PPARalpha response element capable of conferring oleate-mediated transcriptional activation to homologous or heterologous promoters. Electrophoretic mobility shift assays demonstrated that PPARalpha bound FARE-1 with the retinoid X receptor alpha. The expression of M-CPT I in hearts of mice null for PPARalpha was approximately 50% lower than levels in wild-type controls. Moreover, a PPARalpha activator did not induce cardiac expression of the M-CPT I gene in the PPARalpha null mice. These results demonstrate that long-chain fatty acids regulate the transcription of a gene encoding a pivotal enzyme in the mitochondrial fatty acid uptake pathway in cardiac myocytes and define a role for PPARalpha in the control of myocardial lipid metabolism.
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PMID:Fatty acids activate transcription of the muscle carnitine palmitoyltransferase I gene in cardiac myocytes via the peroxisome proliferator-activated receptor alpha. 972 88

Carnitine palmitoyltransferase I (CPT-I) catalyzes the rate-determining step in mitochondrial fatty acid beta-oxidation. CPT-I has two structural genes (alpha and beta) that are differentially expressed among tissues. Our CPT-Ibeta isolates from a human cardiac cDNA library contained two different extreme 5'-sequences derived from short alternative first untranslated exons that utilize a common splice acceptor site in exon 2. Primer extension identified single dominant start sites for each transcript, and ribonuclease protection assays showed the presence of one 5'-exon in liver, muscle, and heart mRNAs, indicating that the cognate promoter U (upstream/ubiquitous) is active in each of these tissues. By contrast, mRNAs containing the alternative 5'-exon were present only in muscle and heart, indicating a muscle-specific promoter M (muscle). CPT-Ibeta mRNA levels increased markedly in tissues of fasted rats, when circulating free fatty acid concentrations are elevated. Using CPT-Ibeta promoter/reporter transient transfection of murine C2C12 myotubes and HepG2 hepatocytes, fatty acids were found to increase promoter activity in a peroxisome proliferator-activated receptor alpha (PPARalpha)-dependent fashion. A promoter fatty acid response element (FARE) was mapped, mutation of which ablated fatty acid-mediated production of both transcripts. PPARalpha/retinoid X receptor alpha formed specific complexes with oligonucleotides containing the FARE, and anti-PPARalpha antibody shifted nuclear protein-DNA complexes, confirming the role of this factor in regulating the expression of this critical metabolic enzyme gene. The constitutive repressor chicken ovalbumin upstream promoter transcription factor competitively binds at the FARE and modulates fatty acid induction of the promoters.
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PMID:Co-regulation of tissue-specific alternative human carnitine palmitoyltransferase Ibeta gene promoters by fatty acid enzyme substrate. 983 40

We have previously demonstrated that dietary fat, especially unsaturated fatty acids, induces cellular retinol-binding protein, type II (CRBPII) gene expression in rat jejunum. In the present study, we showed that feeding a high-fat diet caused parallel increases in jejunal CRBPII mRNA and CRBPII pre-mRNA levels. Nuclear run-on assay also revealed that this increase of CRBPII mRNA level by high-fat diet was, at least in part, triggered at a transcription level. Moreover, peroxisome proliferator-activated receptor alpha (PPARalpha) mRNA level was also increased in the jejunum by high-fat diet. Gel shift assay showed that the binding activity of rat jejunal nuclear protein to the nuclear receptor response elements located in the rat CRBPII gene (RXRE and RE3) was greater in rats fed high-fat diet than in those fed fat-free diet and were enhanced by addition of bacterially expressed PPARalpha protein. Also PPARalpha-retinoid X receptor alpha (RXRalpha) heterodimer was capable of binding to the CRBPII-RXRE and RE3 elements and these binding activities were enhanced by addition of some PPARalpha ligands in the gel shift assay. Taken together, these studies suggest that dietary fatty acids may lead to induction of CRBPII gene transcription through increases of PPARalpha as well as its ligand levels.
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PMID:Transcriptional regulation of cellular retinol-binding protein, type II gene expression in small intestine by dietary fat. 991 40

We previously showed that unsaturated fatty acids induced gene expression of cellular retinol-binding protein type II (CRBPII) in rat jejunum [Suruga, K., Suzuki, R., Goda, T. and Takase, S. (1995) J. Nutr. 125, 2039-2044]. In the present study, we investigated this induction mechanism(s) using the human intestinal Caco-2 cell line. The postconfluent mature Caco-2 cells were maintained in serum-free medium containing arachidonic acid or its analogue, 5,8,11, 14-eicosatetraynoic acid (ETYA). Northern blot analysis showed that these compounds induced CRBPII mRNA levels to rise and that this induction was more effective when combined with 9-cis retinoic acid. This effect was independent of cycloheximide and inhibited by actinomycin D. Nuclear run-on assays confirmed that the ETYA and 9-cis retinoic acid-induced increase of CRBPII mRNA levels was due to an increased rate of transcription of its gene. In Caco-2 cells, the transcripts of peroxisome proliferator-activated receptor alpha (PPARalpha) and retinoid X receptor alpha (RXRalpha), which were activated by their ligands ETYA and 9-cis retinoic acid, respectively, were coexpressed. The gel shift study using rat CRBPII gene nuclear receptor response elements (RXRE, RE2, RE3) revealed that several forms of nuclear proteins from Caco-2 cells specifically bound to these elements. Some of these protein/DNA complexes reacted to both anti-RXRalpha and anti-PPAR antibodies. In addition, in-vitro synthesized RXRalpha and PPARalpha cooperatively bound to these elements as a heterodimer and these binding activities were enhanced by addition of ETYA or arachidonic acid but not by addition of 9-cis retinoic acid. These studies suggest that fatty acid or its analogue may regulate CRBPII gene expression through PPAR/RXR heterodimer bound to the nuclear receptor response element(s) of the CRBPII genes.
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PMID:Regulation of cellular retinol-binding protein type II gene expression by arachidonic acid analogue and 9-cis retinoic acid in caco-2 cells. 1023 66


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