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.
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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.
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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

Previously, we identified a novel transcription factor, ARF6, as a key regulator of the tissue-specific adipocyte P2 (aP2) enhancer. In order to identify the proteins which comprise the adipocyte ARF6 complex, we have purified this DNA binding activity from a cultured adipocyte cell line. We have developed a system for growth and differentiation of HIB-1B brown adipocytes in suspension culture that facilitates the production of large quantities of adipocyte nuclear extract. ARF6 was purified from HIB-1B nuclear extract by a combination of conventional and sequence-specific DNA affinity chromotography. Chemical sequencing and mass spectral analysis of tryptic peptides derived from the purified polypeptides identifies the ARF6 complex as a heterodimer of the retinoid X receptor alpha (RXR alpha) and the murine peroxisome proliferator activated receptor gamma (PPAR gamma). Of the known PPAR gamma isoforms, PPAR gamma is the predominant form expressed in adipose tissue. These results suggest that PPAR gamma 2 serves a unique function among PPAR family members as an important regulator of adipocyte-specific gene expression.
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PMID:Adipocyte-specific transcription factor ARF6 is a heterodimeric complex of two nuclear hormone receptors, PPAR gamma and RXR alpha. 783 15

We have isolated a human peroxisomal proliferator activated receptor (hPPAR) from a human liver cDNA library. Based on sequence analysis, we have determined that this cDNA encodes the human PPAR alpha. When assayed in a reconstituted hPPAR responsive transcription system in mammalian CV-1 cells, this receptor was shown to be transcriptionally activated by hypolipidemic agents like clofibric acid, and ETYA (5,8,11,14-eicosatetraynoic acid; a synthetic arachidonic acid homolog). When analyzed in CV-1 cells, the rat PPAR alpha was similarly transcriptionally regulated. However, when assayed in a human liver cell line (HepG2) we noticed that ETYA was a more efficient activator of hPPAR alpha than rPPAR alpha. Thus, factors other than the receptor are important in determining the cellular responsiveness to this class of compounds. Interestingly, WY-14,643, another peroxisome proliferator, was a much more potent activator of rPPAR alpha than human PPAR alpha when assayed in both cell lines. This may explain in part why certain fibrates are potent hepatocarcinogens in rodents. Northern analysis indicates that hPPAR alpha and rPPAR alpha are well expressed in heart, kidney and liver. We further demonstrate that hPPAR alpha and human retinoid X receptor alpha synergistically interact to bind and transactivate through a peroxisomal proliferator response element. Thus in a similar cell and promoter context the rat and human PPARs show a differential response to certain activators. Cumulatively these data suggest that differential ligand responsiveness does not provide a complete explanation for the different biological effects exhibited by hypolipidemic drugs when administered to humans and rats.
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PMID:Human and rat peroxisome proliferator activated receptors (PPARs) demonstrate similar tissue distribution but different responsiveness to PPAR activators. 798 Nov 25

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 cloned a human cognate of the mouse peroxisome-proliferator-activated receptor-gamma (hPPAR gamma) from a human placenta cDNA library. Sequence analysis reveals a high degree of similarity with the mouse receptor and, like other PPAR, hPPAR gamma forms heterodimers with the retinoid X receptor alpha (RXR alpha) and binds in vitro to DNA elements containing direct repeats of the sequence TGACCT. In common with mouse PPAR gamma, hPPAR gamma is expressed strongly in adipose tissue, but significant levels also are detectable in placenta, lung and ovary. In vitro trans-activation data suggest hPPAR gamma is only poorly activated by xenobiotic peroxisome proliferators, although certain fatty acids and eicosanoids are potent activators of this receptor. Both mouse and human PPAR gamma are capable of being activated by thiazolidinedione drugs, although the two receptors appear to differ in their sensitivity to these compounds. Taken together, these data suggest a high degree of structural and functional similarity between mouse and human PPAR gamma, and provide evidence for variation in human receptor structure which may result in differential sensitivity to activators.
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PMID:A human peroxisome-proliferator-activated receptor-gamma is activated by inducers of adipogenesis, including thiazolidinedione drugs. 870 92

Induction of terminal differentiation represents a promising therapeutic approach to certain human malignancies. The peroxisome proliferator-activated receptor gamma (PPAR gamma) and the retinoid X receptor alpha (RXR alpha) form a heterodimeric complex that functions as a central regulator of adipocyte differentiation. Natural and synthetic ligands for both receptors have been identified. We demonstrate here that PPAR gamma is expressed at high levels in each of the major histologic types of human liposarcoma. Moreover, primary human liposarcoma cells can be induced to undergo terminal differentiation by treatment with the PPAR gamma ligand pioglitazone, suggesting that the differentiation block in these cells can be overcome by maximal activation of the PPAR pathway. We further demonstrate that RXR-specific ligands are also potent adipogenic agents in cells expressing the PPAR gamma/RXR alpha heterodimer, and that simultaneous treatment of liposarcoma cells with both PPAR gamma- and RXR-specific ligands results in an additive stimulation of differentiation. Liposarcoma cell differentiation is characterized by accumulation of intracellular lipid, induction of adipocyte-specific genes, and withdrawal from the cell cycle. These results suggest that PPAR gamma ligands such as thiazolidinediones and RXR-specific retinoids may be useful therapeutic agents for the treatment of liposarcoma.
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PMID:Terminal differentiation of human liposarcoma cells induced by ligands for peroxisome proliferator-activated receptor gamma and the retinoid X receptor. 899 Jan 92

Fatty acid transport protein (FATP), a plasma membrane protein implicated in controlling adipocyte transmembrane fatty acid flux, is up-regulated as a consequence of adipocyte differentiation and down-regulated by insulin. Based upon the sequence of the FATP gene upstream region (Hui, T. Y., Frohnert, B. I., Smith, A. J., Schaffer, J. A., and Bernlohr, D. A. (1998) J. Biol. Chem. 273, 27420-27429) a putative peroxisome proliferator-activated receptor response element (PPRE) is present from -458 to -474. To determine whether the FATP PPRE was functional, and responded to lipid activators, transient transfection of FATP-luciferase reporter constructs into CV-1 and 3T3-L1 cells was carried out. In CV-1 cells, FATP-luciferase activity was up-regulated 4- and 5.5-fold, respectively, by PPARalpha and PPARgamma in the presence of their respective activators in a PPRE-dependent mechanism. PPARdelta, however, was unable to mediate transcriptional activation under any condition. In 3T3-L1 cells, the PPRE conferred a small but significant increase in expression in preadipocytes, as well as a more robust up-regulation of FATP expression in adipocytes. Furthermore, the PPRE conferred the ability for luciferase expression to be up-regulated by activators of both PPARgamma and retinoid X receptor alpha (RXRalpha) in a synergistic manner. PPARalpha and PPARdelta activators did not up-regulate FATP expression in 3T3-L1 adipocytes, however, suggesting that these two subtypes do not play a significant role in differentiation-dependent activation in fat cells. Electromobility shift assays showed that all three PPAR subtypes were able to bind specifically to the PPRE as heterodimers with RXRalpha. Nuclear extracts from 3T3-L1 adipocytes also showed a specific gel-shift complex with the FATP PPRE. To correlate the expression of FATP to its physiological function, treatment of 3T3-L1 adipocytes with PPARgamma and RXRalpha activators resulted in an increased uptake of oleate. Moreover, linoleic acid, a physiological ligand, up-regulated FATP expression 2-fold in a PPRE-dependent manner. These results demonstrate that the FATP gene possesses a functional PPRE and is up-regulated by activators of PPARalpha and PPARgamma, thereby linking the activity of the protein to the expression of its gene. Moreover, these results have implications for the mechanism by which certain PPARgamma activators such as the antidiabetic thiazolidinedione drugs affect adipose lipid metabolism.
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PMID:Identification of a functional peroxisome proliferator-responsive element in the murine fatty acid transport protein gene. 993 87

Complex physiological stimuli differentially regulate the tissue-specific transcription of the lipoprotein lipase (LPL) gene. A conserved DNA recognition element (-171 to -149 bp) within the promoter functions as a transcriptional enhancer when bound by the peroxisome proliferator-activated receptor-gamma2 (PPARgamma2)/retinoid X receptor alpha (RXRalpha) heterodimer, but serves as a transcriptional silencer in the presence of unidentified double and single stranded DNA-binding proteins. To address this apparent paradox, the current study examined the effect of two classes of candidate comodulatory proteins, COUP-TF (chicken ovalbumin upstream promoter transcriptional factor) and the corepressor SMRT (silencing mediator of retinoic acid receptor and thyroid receptor). The expression of COUP-TF was detected by Western and Northern blots in a preadipocyte 3T3-L1 cell model during periods corresponding to increased LPL transcription. Cotransfection of COUP-TF expression constructs in the renal epithelial 293T cell line significantly increased transcription from the LPL promoter in synergy with PPARgamma2/RXRalpha heterodimers. The COUP-TFII (ARP-1) protein specifically bound the LPL PPAR recognition element inelectromobility shift assays and interacted directly with the ligand-binding domain of PPARgamma in pull-down experiments. In contrast, cotransfection of SMRT repressed PPARgamma2/ RXRalpha-mediated LPL transcription in the absence or presence of COUP-TFII (ARP-1). The interaction between PPARgamma2 and SMRT localized to the receptor-interactive domain 2 (amino acids 1260-1495) of the SMRT protein based on cotransfection and pull-down assays. These in vitro data indicate that COUP-TF proteins and SMRT modulate PPARgamma-mediated LPL transcription in the 293T cell line.
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PMID:A corepressor and chicken ovalbumin upstream promoter transcriptional factor proteins modulate peroxisome proliferator-activated receptor-gamma2/retinoid X receptor alpha-activated transcription from the murine lipoprotein lipase promoter. 1009 92


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