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)

Adrenocorticotropic hormone can stimulate lipolysis and suppress leptin expression in murine adipocytes. These effects are mediated via the melanocortin 2 receptor (MC2-R), which is expressed when 3T3-L1 cells are induced to undergo adipogenesis. In this study, we have characterized the mc2-r promoter in the murine adipocyte, one of the few extra-adrenal sites of expression and a cell type that lacks steroidogenic factor 1 (SF-1), a transcription factor that is required for mc2-r expression in adrenal cells. Transcriptional regulation of the mc2-r in the absence of SF-1 was investigated by 5' deletion analysis of the murine mc2-r promoter in both undifferentiated and differentiated 3T3-L1 cells. The results revealed the presence of a 59-base pair regulatory region within the promoter containing an adipocyte-specific enhancer. The ability of this region to confer enhanced activity in the adipocyte was mapped to a peroxisome proliferator-response element (PPRE)-like sequence that bound to peroxisome proliferator-activated receptor gamma (PPARgamma) and its heterodimeric partner retinoid X receptor alpha (RXRalpha) in adipocyte nuclear extracts. Co-transfection of PPARgamma2/RXRalpha with the pMC2-R(-112/+105)GL3 reporter resulted in transcriptional activation in preadipocytes, and this response required an intact PPRE. Mutation of the PPRE to prevent PPARgamma/RXRalpha binding resulted in a complete abrogation of the pMC2-R(-112/+105)GL3 reporter activity in day 3 differentiated 3T3-L1 cells, demonstrating a key role played by this site in regulating MC2-R expression in the murine adipocyte. These data highlight a novel mechanism for mc2-r transcription, which may have significance in both adrenal and extra-adrenal sites of expression.
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PMID:A peroxisome proliferator-response element in the murine mc2-r promoter regulates its transcriptional activation during differentiation of 3T3-L1 adipocytes. 1502 12

The nuclear bile acid receptor FXR (farnesoid X receptor) is one of the key factors that suppress bile acid biosynthesis in the liver. PGC-1alpha [PPARgamma (peroxisome-proliferator-activated receptor gamma) co-activator-1alpha] is known to control energy homoeostasis in adipose tissue, skeletal muscle and liver. We performed cell-based reporter assays using the expression system of a GAL4-FXR chimaera, the ligand-binding domain of FXR fused to the DNA-binding domain of yeast GAL4, to find the co-activators for FXR. We found that the transcriptional activation of a reporter plasmid by a GAL4-FXR chimaera was strongly enhanced by PGC-1alpha, in a ligand-dependent manner. Transcriptional activation of the SHP (small heterodimer partner) gene by the FXR-RXRalpha (retinoid X receptor alpha) heterodimer was also enhanced by PGC-1alpha in the presence of CDCA (chenodeoxycholic acid). Co-immunoprecipitation and pull-down studies using glutathione S-transferase-PGC-1alpha fusion proteins revealed that the ligand-binding domain of FXR binds PGC-1alpha in a ligand-influenced manner both in vivo and in vitro. Furthermore, our studies revealed that SHP represses its own transcription, and the addition of excess amounts of PGC-1alpha can overcome the inhibitory effect of SHP. These observations indicate that PGC-1alpha mediates the ligand-dependent activation of FXR and transcription of SHP gene.
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PMID:The nuclear bile acid receptor FXR is activated by PGC-1alpha in a ligand-dependent manner. 1520 34

Peroxisome proliferator-activated receptor gamma (PPARgamma) is involved in the control of cell proliferation, apoptosis and differentiation in various tumor cells. Among PPARgamma ligands, 15-deoxy-Delta12,14-prostaglandin J2 (PGJ2), the ultimate metabolite of PGD2, plays a role in the biology of brain tumors. It is still unclear to which extent the anti-proliferative and differentiation-promoting activity of PGJ2 is mediated through PPARgamma. We compared the effects of PGJ2 with those of rosiglitazone - the synthetic agonist with the highest affinity for PPARgamma - in 4 human glioblastoma cell lines (A172, U87-MG, M059K, M059J). All cell lines expressed high levels of PPARgamma, consistent with the high levels of PPARgamma protein in 5 tumor samples. Both PGJ2 and rosiglitazone inhibited proliferation of all cell lines with a G2/M arrest and apoptosis, but only PGJ2 up-regulated p21Cip/WAF1. The growth inhibitory effect was partially reversed by the PPARgamma antagonist GW9662. We studied the time sequence of selected molecular events, that lead glioblastoma cells to apoptosis and/or differentiation, after treatment with both agonists. M059K cells committed to undergo apoptosis by PGJ2, initially up-regulated PPARgamma, and then down-regulated PPARgamma as they began apoptosis. Apoptotic cells also increased their expression of retinoic acid receptor beta (RARbeta) and retinoid X receptor alpha (RXRalpha). PGJ2 increased expression of glial fibrillary acidic protein (GFAP) and decreased levels of vimentin, structural proteins modulated during astrocytic differentiation. Unexpectedly, PGJ2 up-regulated the expression of cyclooxygenase-2 (COX-2). Rosiglitazone caused the same pattern of PPARgamma, RARbeta and RXRalpha expression as PGJ2, but no significant modulation of p21Cip/WAF1, cytoskeletal proteins or COX-2 occurred. Our data indicate that PGJ2, and rosiglitazone suppress cell proliferation and cause apoptosis in glioblastoma cell lines, most likely through a PPARgamma-dependent pathway. By contrast, the modulation of differentiation-associated proteins by PGJ2, but not rosiglitazone, suggests that PGJ2 promotes differentiation of glioblastoma cells independently of PPARgamma activation.
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PMID:The PPARgamma ligands PGJ2 and rosiglitazone show a differential ability to inhibit proliferation and to induce apoptosis and differentiation of human glioblastoma cell lines. 1525 49

The common commercial use of phthalate esters has resulted in significant human exposure to these bioactive compounds. The facts that phthalate ester metabolites, like endogenous PGs, are peroxisome proliferator-activated receptor (PPAR) agonists, and that PPARgamma agonists induce lymphocyte apoptosis suggest that phthalate esters are immunosuppressants that could act together with PGs to modulate early B cell development. In this study we examined the effects of a metabolite of one environmental phthalate, mono(2-ethylhexyl)phthalate (MEHP), and 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)), on developing B cells. MEHP inhibited [(3)H]thymidine incorporation by primary murine bone marrow B cells and a nontransformed murine pro/pre-B cell line (BU-11). Cotreatment with a retinoid X receptor alpha ligand, 9-cis-retinoic acid, decreased [(3)H]thymidine incorporation synergistically, thereby implicating activation of a PPARgamma-retinoid X receptor alpha complex. These results were similar to those obtained with the natural PPARgamma ligand 15d-PGJ(2). At moderate MEHP concentrations (25 or 100 microM for primary pro-B cells and a pro/pre-B cell line, respectively), inhibition of [(3)H]thymidine incorporation resulted primarily from apoptosis induction, whereas at lower concentrations, the inhibition probably reflected growth arrest without apoptosis. Cotreatment of bone marrow B cells with 15d-PGJ(2) and MEHP significantly enhanced the inhibition of [(3)H]thymidine incorporation seen with MEHP alone, potentially mimicking exposure in the bone marrow microenvironment where PG concentrations are high. Finally, MEHP- and 15d-PGJ(2)-induced death does not result from a decrease in NF-kappaB activation. These data demonstrate that environmental phthalates can cooperate with an endogenous ligand, 15d-PGJ(2), to inhibit proliferation of and induce apoptosis in developing bone marrow B cells, potentially via PPARgamma activation.
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PMID:Environmental and endogenous peroxisome proliferator-activated receptor gamma agonists induce bone marrow B cell growth arrest and apoptosis: interactions between mono(2-ethylhexyl)phthalate, 9-cis-retinoic acid, and 15-deoxy-Delta12,14-prostaglandin J2. 1532 77

CBP, cAMP-response element-binding protein (CREB)-binding protein, plays an important role as a general cointegrator of various signaling pathways and interacts with a large number of transcription factors. Interactions of CBP with ligand binding domains (LBDs) of nuclear receptors are mediated by LXXLL motifs, as are those of p160 proteins, although the number, distribution, and precise sequences of the motifs differ. We used a large N-terminal fragment of murine CBP to map by biochemical methods and NMR spectroscopy the interaction domain of CBP with the LBDs of several nuclear receptors. We show that distinct zones of that fragment are involved in the interactions: a 20-residue segment containing the LXXLL motif (residues 61-80) is implicated in the interaction with all three domains tested (peroxisome proliferator-activated receptor gamma-LBD, retinoid X receptor alpha-LBD, and estrogen-related receptor gamma-LBD), whereas a second N-terminal well conserved block of around 25 residues centered on a consensus L(40)PDEL(44) motif constitutes a secondary motif of interaction with peroxisome proliferator-activated receptor gamma-LBD. Sequence analysis reveals that both zones are well conserved in all vertebrate p300/CBP proteins, suggesting their functional importance. Interactions of p300/CBP coactivators with the LBDs of nuclear receptors are not limited to the canonical LXXLL motifs, involving both a longer contiguous segment around the motif and, for certain domains, an additional zone.
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PMID:Biochemical and NMR mapping of the interface between CREB-binding protein and ligand binding domains of nuclear receptor: beyond the LXXLL motif. 1554 61

All-trans retinoic acid (ATRA) potently inhibits the differentiation of porcine preadipocytes in primary culture; however, the mechanism by which ATRA exerts this effect in pigs is poorly understood. The objective of this study was to use retinoid receptor-specific ligands to investigate the mechanism underlying the antiadipogenic action of retinoids in cultured pig preadipocytes by identifying the retinoid receptor mediating this action and examining the effect of retinoids on the expression of key adipogenic transcription factors. Stromal-vascular cells were harvested from porcine adipose tissue and cultured in serum-free medium. Glycerol-3-phoshphate dehydrogenase (GPDH) activity, a late marker of preadipocyte differentiation, was decreased (P < 0.01) by the addition of 0 to 10 microM of either ATRA, a nonspecific agonist for both the retinoic acid receptor (RAR) and the retinoid X receptor (RXR) or the selective RAR agonist, 4-(E-2-[5,6,7,8-tet-rahydro-5,5,8,8-tetramethyl-2-naphthalenyl]-1-propenyl) benzoic acid (TTNPB). Addition of increasing amounts of Ro-61, a RAR-specific antagonist (0 to 10 microM) prevented ATRA and TTNBP from decreasing GPDH activity. Addition of methoprene acid, an RXR-specific agonist, increased (P < 0.01) GPDH activity. Preadipocytes were then continuously treated with 10 nM of TTNPB in the presence or absence of 1 microM Ro-61, and mRNA was isolated on d 2 and 8. Addition of TTNPB decreased (P < 0.001) the expression of peroxisome proliferator-activated receptor gamma (PPARgamma), sterol regulatory element-binding protein-1c (SREBP-1c), retinoid X receptor alpha (RXRalpha), and adipocyte fatty acid binding protein (aP2) mRNA transcripts, whereas these effects were prevented by the presence of Ro-61. Interestingly, TTNBP increased (P < 0.001) the mRNA abundance of the orphan nuclear receptor chicken ovalbumin upstream promoter-transcription factor 1 (COUP-TF1), whereas Ro-61 prevented this increase. These changes were independent of alterations in the mRNA abundances of the retinoic acid receptor alpha, and CCAAT/enhancer binding protein alpha and beta (C/EBPbeta; C/EBPalpha) genes. These results indicate that retinoic acid inhibits porcine preadipocyte differentiation by a mechanism that involves activation of the RAR and downregulation of PPARgamma, RXRalpha, and SREBP-1C mRNA. This mechanism is independent of changes in C/EBPbeta and C/EBPalpha mRNA abundance and may involve COUP-TF.
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PMID:Regulation of differentiating pig preadipocytes by retinoic acid. 1558 48

BACKGROUND: There is a substantial clinical overlap between chronic renal failure (CRF) and hypothyroidism, suggesting the presence of hypothyroidism in uremic patients. Although CRF patients have low T3 and T4 levels with normal thyroid-stimulating hormone (TSH), they show a higher prevalence of goiter and evidence for blunted tissue responsiveness to T3 action. However, there are no studies examining whether thyroid hormone receptors (TRs) play a role in thyroid hormone dysfunction in CRF patients. To evaluate the effects of an uremic environment on TR function, we investigated the effect of uremic plasma on TRbeta1 binding to DNA as heterodimers with the retinoid X receptor alpha (RXRalpha) and on T3-dependent transcriptional activity. RESULTS: We demonstrated that uremic plasma collected prior to hemodialysis (Pre-HD) significantly reduced TRbeta1-RXRalpha binding to DNA. Such inhibition was also observed with a vitamin D receptor (VDR) but not with a peroxisome proliferator-activated receptor gamma (PPARgamma). A cell-based assay confirmed this effect where uremic pre-HD ultrafiltrate inhibited the transcriptional activation induced by T3 in U937 cells. In both cases, the inhibitory effects were reversed when the uremic plasma and the uremic ultrafiltrate were collected and used after hemodialysis (Post-HD). CONCLUSION: These results suggest that dialyzable toxins in uremic plasma selectively block the binding of TRbeta1-RXRalpha to DNA and impair T3 transcriptional activity. These findings may explain some features of hypothyroidism and thyroid hormone resistance observed in CRF patients.
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PMID:Thyroid hormone receptor binding to DNA and T3-dependent transcriptional activation are inhibited by uremic toxins. 1580 94

Peroxisome proliferator-activated receptor gamma (PPARgamma) plays a critical albeit poorly defined role in the development and progression of several cancer types including those of the breast, colon, and lung. A PPAR response element (PPRE) reporter assay was utilized to evaluate the selective transactivation of PPARgamma in 10 different cell lines including normal mammary epithelial, breast, lung, and colon cancer cells. Cells were treated with one of four compounds including rosglitizone (Ros), ciglitizone (Cig), 15-deoxy-Delta(12,14)-prostaglandin J2 (PGJ2), or GW 9662 (GW). We observed differences in transactivation between cell lines from different tissue origin, across cell lines from a single tissue type, and selective modulation of PPARgamma within a single cell line by different ligands. Interestingly, GW, a PPARgamma antagonist in adipocytes, enhanced PPRE reporter activation in normal mammary epithelial cells while it had virtually no effect in any of the cancer cell lines tested. Within each cancer type, individual cell lines were found to respond differently to distinct PPARgamma ligands. For instance, Ros, Cig, and PGJ2 were all potent agonist of PPARgamma transactivation in lung adenocarcinoma cell lines while these same ligands had no effect in squamous cell or large cell carcinomas of the lung. Message levels of PPARgamma and retinoid X receptor alpha (RXRalpha) in the individual cell lines were quantitated by real time-polymerase chain reaction (RT-PCR). The ratio of PPARgamma to RXRalpha was predictive of how cells responded to co-treatment of Ros and 9-cis-retinoic acid, an RXRalpha agonist, in two out of three cell lines tested. These data indicate that PPARgamma can be selectively modulated and suggests that it may be used as a therapeutic target for individual tumors.
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PMID:Selective activation of PPARgamma in breast, colon, and lung cancer cell lines. 1586 24

Fatty acids (FAs) are known to be important regulators of insulin secretion from pancreatic beta-cells. FA-coenzyme A esters have been shown to directly stimulate the secretion process, whereas long-term exposure of beta-cells to FAs compromises glucose-stimulated insulin secretion (GSIS) by mechanisms unknown to date. It has been speculated that some of these long-term effects are mediated by members of the peroxisome proliferator-activated receptor (PPAR) family via an induction of uncoupling protein-2 (UCP2). In this study we show that adenoviral coexpression of PPARalpha and retinoid X receptor alpha (RXRalpha) in INS-1E beta-cells synergistically and in a dose- and ligand-dependent manner increases the expression of known PPARalpha target genes and enhances FA uptake and beta-oxidation. In contrast, ectopic expression of PPARgamma/RXRalpha increases FA uptake and deposition as triacylglycerides. Although the expression of PPARalpha/RXRalpha leads to the induction of UCP2 mRNA and protein, this is not accompanied by reduced hyperpolarization of the mitochondrial membrane, indicating that under these conditions, increased UCP2 expression is insufficient for dissipation of the mitochondrial proton gradient. Importantly, whereas expression of PPARgamma/RXRalpha attenuates GSIS, the expression of PPARalpha/RXRalpha potentiates GSIS in rat islets and INS-1E cells without affecting the mitochondrial membrane potential. These results show a strong subtype specificity of the two PPAR subtypes alpha and gamma on lipid partitioning and insulin secretion when systematically compared in a beta-cell context.
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PMID:Peroxisome proliferator-activated receptor alpha (PPARalpha) potentiates, whereas PPARgamma attenuates, glucose-stimulated insulin secretion in pancreatic beta-cells. 1600 73

Aromatase inhibitors target the production of estrogen in breast adipose tissue, but in doing so, also decrease estrogen formation in bone and other sites, giving rise to deleterious side effects, such as bone loss and arthralgia. Thus, it would be clinically useful to selectively inhibit aromatase production in breast. In this regard, we have determined that the orphan nuclear receptor liver receptor homologue-1 (LRH-1) is a specific transcriptional activator of aromatase gene expression in human breast preadipocytes but not in other tissues of postmenopausal women. In this study, we show that the coactivator peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) is a physiologically relevant modulator of LRH-1, and that its transcriptional activity can be inhibited effectively using receptor-interacting peptide antagonists that prevent PGC-1alpha recruitment. Interestingly, we note that all of these peptides also interact in an agonist-dependent manner with retinoid X receptor alpha (RXRalpha), suggesting that these two receptors may compete for limiting cofactors within target cells. In support of this hypothesis, we show that 9-cis-retinoic acid, acting through RXR, inhibits both the basal and PGC-1alpha-induced transcriptional activity of LRH-1. The importance of this finding was confirmed by showing that LRH-1-dependent, PGC-1alpha-stimulated regulation of aromatase gene expression in primary human breast preadipocytes was effectively suppressed by RXR agonists. We infer from these data that LRH-1 is a bona fide target whose inhibition would selectively block aromatase expression in breast, while sparing other sites of expression.
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PMID:Coactivation of liver receptor homologue-1 by peroxisome proliferator-activated receptor gamma coactivator-1alpha on aromatase promoter II and its inhibition by activated retinoid X receptor suggest a novel target for breast-specific antiestrogen therapy. 1635 89


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