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

We have isolated a cDNA corresponding to the hamster peroxisome proliferator-activated receptor haPPAR gamma, a member of the steroid nuclear hormone receptor superfamily of transcription factors. haPPAR gamma mRNA is highly expressed in adipose tissue, and is expressed in lung, heart, kidney, liver and spleen to a lower extent. Thus, haPPAR gamma may function in activating the transcription of target genes in a variety of tissues, including those not particularly subjected to peroxisomal beta-oxidation. haPPAR gamma binds efficiently in the presence of retinoid X receptor alpha (RXR alpha) to a peroxisome proliferator response element (PPRE) first identified in the acyl-CoA oxidase (ACO) promoter, the rate-limiting enzyme of peroxisomal beta-oxidation. The gene (ACO) encoding this enzyme has been previously shown to be under the transcriptional control of mouse PPAR (mPPAR). Although binding of haPPAR gamma/RXR alpha on the PPRE of the ACO promoter in vitro is similar to that observed for mPPAR/RXR alpha, we show that the transcriptional activities of mPPAR and haPPAR gamma are regulated differently in vivo in response to peroxisome proliferators and heterodimerization with RXR.
Gene 1995 Sep 11
PMID:cDNA cloning and characterization of the transcriptional activities of the hamster peroxisome proliferator-activated receptor haPPAR gamma. 755 47

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.
Mol Pharmacol 1995 Sep
PMID:A single amino acid change in the mouse peroxisome proliferator-activated receptor alpha alters transcriptional responses to peroxisome proliferators. 756 38

Transcription of the late genes of simian virus 40 (SV40) is repressed during the early phase of the lytic cycle of infection of binding of cellular factors, called IBP-s, to the SV40 late promoter; repression is relieved after the onset of viral DNA replication by titration of these repressors. Preliminary data indicated that one of the major components of IBP-s was human estrogen-related receptor 1 (hERR1). We show here that several members of the steroid/thyroid hormone receptor superfamily, including testis receptor 2, thyroid receptor alpha 1 in combination with retinoid X receptor alpha, chicken ovalbumin upstream promoter transcription factors 1 and 2 (COUP-TF1 and COUP-TF2), as well as hERR1, possess the properties of IBP-s. These receptors bind specifically to hormone receptor binding sites present in the SV40 major late promoter. Recombinant COUP-TF1 specifically represses transcription from the SV40 major late promoter in a cell-free transcription system. Expression of COUP-TF1, COUP-TF2, or hERR1 in monkey cells results in repression of the SV40 late promoter, but not the early promoter, in the absence of the virally encoded large tumor antigen. Overexpression of COUP-TF1 leads to a delay in the early-to-late switch in SV40 gene expression during the lytic cycle of infection. Thus, members of this superfamily can play major direct roles in regulating expression of SV40. Possibly, natural or synthetic ligands to these receptors can serve as antiviral drugs. Our findings also provide the basis for the development of assays to screen for the ligands to testis receptor 2 and hERR1.
Proc Natl Acad Sci U S A 1995 Sep 12
PMID:Simian virus 40 late gene expression is regulated by members of the steroid/thyroid hormone receptor superfamily. 756 79

Hepatocyte nuclear factor 4 (HNF-4), a highly conserved member of the steroid hormone receptor superfamily critical for development and liver-specific gene expression, is very similar to another superfamily member, retinoid X receptor alpha (RXR alpha), in overall amino acid sequence and DNA binding specificity. Since RXR alpha is known to heterodimerize with many other nuclear receptors, the formation of heterodimers between HNF-4 and RXR alpha was examined. With the electrophoretic mobility shift assay, coimmunoprecipitation, and transient transfection assays, it is shown that, unlike other nuclear receptors, HNF-4 does not form heterodimers with RXR alpha either in the presence or in the absence of DNA. We also show that in vitro-translated HNF-4 does not form heterodimeric complexes on DNA with a number of other receptors, including RXR beta, RXR gamma, retinoic acid receptor alpha, or thyroid hormone receptor alpha. To investigate the hypothesis that the lack of heterodimerization between HNF-4 and RXR alpha is due to a strong homodimerization activity of HNF-4, glycerol gradient sedimentation and kinetic analysis were used to show that HNF-4 is in fact a stable homodimer in solution. Finally, immunohistochemistry is used to show that the HNF-4 protein is found exclusively in the nuclei in both HepG2 cells, which express endogenous HNF-4, and transfected COS cells, which overexpress HNF-4. These findings lead us to propose that HNF-4 defines a new subclass of nuclear receptors which reside primarily in the nucleus and which bind DNA and regulate transcription as homodimers.
Mol Cell Biol 1995 Sep
PMID:Exclusive homodimerization of the orphan receptor hepatocyte nuclear factor 4 defines a new subclass of nuclear receptors. 765 30

Acyl-CoA-binding protein (ACBP) is an ubiquitously expressed 10-kDa protein which is present in high amounts in cells involved in solute transport or secretion. Rat ACBP is encoded by a gene containing the typical hallmarks of a housekeeping gene. Analysis of the promoter region of the rat ACBP gene by electrophoretic mobility shift assay (EMSA) revealed specific binding of proteins from rat liver nuclear extracts to potential recognition sequences of NF-1/CTF, Sp1, AP-1, C/EBP and HNF-3. In addition, specific binding to a DR-1 type element was observed. By using in vitro translated peroxisome proliferator activated receptors (PPAR) and a retinoid X receptor alpha (RXRalpha), we demonstrated that this DR-1 element was capable of binding PPARalpha/RXRalpha, PPARdelta/RXRalpha and PPARgamma2/RXRalpha heterodimers. The PPARgamma2/RXRalpha heterodimer appeared to have the highest affinity for the ACBP DR-1 element. Addition of peroxisome proliferators (PP) to H4IIEC3 rat hepatoma cells led to an increase in the ACBP mRNA level, indicating that the DR-1 element could be a functional peroxisome proliferator responsive element (PPRE). Analysis of the ACBP promoter by transient transfection showed that deletion of the region containing the DR-1 element reduced transcriptional activity, and further indicated that three AP-2 sites and one NF-1/CTF site in the proximal promoter are of importance for basal promoter activity.
Gene 1996 Sep 16
PMID:Regulatory elements in the promoter region of the rat gene encoding the acyl-CoA-binding protein. 896 5

Although mutations of human thyroid hormone receptor beta (hTR beta) have been associated with resistance to thyroid hormone (RTH), the molecular basis by which the mutant TRs cause the various clinical symptoms is unknown. We show here that a mutant TR beta [corrected] identified in a patient with RTH inhibited the transcriptional activities of, not only the wild-type TR beta, but also other nuclear receptors including retinoid X receptor alpha (RXR alpha), vitamin D3 receptor (VDR) and retinoic acid receptor (RAR alpha). We provide evidence that these inhibitions by the mutant TR beta [corrected] occur by different mechanisms. Namely, the mutant TR beta interferes with VDR and RAR alpha by competition for binding to the corresponding response elements, but the pathway through RXR alpha is mainly inhibited by squelching of RXR alpha in solution. These findings suggest that in patients with RTH, not only the T3 responsive genes but also other responsive genes are inhibited by the mutant TRs, which might explain the variety of clinical symptoms in RTH.
Biochem Biophys Res Commun 1997 Sep 08
PMID:A mutant thyroid hormone receptor beta 1 identified in a patient with resistance to thyroid hormone inhibits the activities of not only the wild-type TRs, but also other nuclear receptors. 929 47

Mutations of a single residue in the retinoid X receptor alpha (RXRalpha) ligand-binding pocket (LBP) generate constitutive, ligand-binding-competent mutants with structural and functional characteristics similar to those of agonist-bound wild-type RXR. Modelling of the mouse RXRalphaF318A LBP suggests that, like agonist binding, the mutation disrupts a cluster of van der Waals interactions that maintains helix H11 in the apo-receptor location, thereby shifting the thermodynamic equilibrium to the holo form. Heterodimerization with some apo-receptors (retinoic acid, thyroid hormone and vitamin D3 receptors) results in 'silencing' of RXRalphaF318A constitutive activity, which, on the other hand, efficiently contributes to synergistic transactivation within NGFI-B-RXR heterodimers. RAR mutants disabled for corepressor binding and/or lacking a functional AF-2 activation domain, do not relieve RXR 'silencing'. Not only RAR agonists, but also the RAR antagonist BMS614 induce conformational changes allowing RXR to exert constitutive (RXRalphaF318A) or agonist-induced (wild-type RXR) activity in heterodimers. Interestingly, the RXRalphaF318A constitutive activity generated within heterodimers in the presence of BMS614 requires the integrity of both RXR and RAR AF-2 domains. These observations suggest that, within RXR-RAR heterodimers, RAR can adopt a structure distinct from that of the active holo-RAR, thus allowing RXR to become transcriptionally responsive to agonists.
EMBO J 1997 Sep 15
PMID:A mutation mimicking ligand-induced conformational change yields a constitutive RXR that senses allosteric effects in heterodimers. 931 28

Hepatitis B virus (HBV) enhancer I has been shown to consist of several cis-acting sequences for the HBV gene expression efficiently in certain types of cells. Transcriptional regulation of HBV X gene mediated by enhancer I might be one of the mechanisms by which HBV obtains hepatotropism. By mutagenesis analysis of enhancer I function in the enhancer I/X gene promoter complex, we characterized a specific transcriptional regulatory region (designated as a LSR element, nt 989-1030) of enhancer I for the X gene promoter by means of the transient transfection technique using hepatic and nonhepatic cells. Based on the analysis of protein factors interacting with the LSR element, liver-enriched transcriptional factors, HNF3 and HNF4 or retinoid X receptor alpha (RXR alpha), are probably implicated in the activity of enhancer I for the efficient expression of X gene through their interaction with the LSR element in the hepatic cell. Furthermore, the isolated LSR element was demonstrated to function alone as a specific cis-acting element and to be able to activate transcription from the X gene promoter efficiently in the hepatic cell in an orientation-independent manner.
Virology 1997 Sep 29
PMID:Characterization of a specific region in the hepatitis B virus enhancer I for the efficient expression of X gene in the hepatic cell. 932 35

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.
J Biol Chem 1998 Sep 11
PMID:Fatty acids activate transcription of the muscle carnitine palmitoyltransferase I gene in cardiac myocytes via the peroxisome proliferator-activated receptor alpha. 972 88

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.
J Biol Chem 1999 Sep 03
PMID:Evidence for a novel cardiac-enriched retinoid X receptor partner. 1046 3


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