Disease relevance of RXRA

• 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 [1].
• Interestingly, LE550 induced AP-1 activity when RARbeta and RXRalpha were expressed in HeLa cells but not in breast cancer cells [2].
• Moreover, the LDLR promoter contained an LXR response element that was recognized by LXRalpha/RXRalpha (retinoid X receptor alpha) heterodimers in hepatoblastoma cells [3].
• The PLC/PRF/5 and HuH7 hepatoma cell lines expressed retinoid X receptor-alpha (RXR alpha) mRNA, whose expression was constitutive [4].
• Our findings suggest that activation of PPARgamma/RXRalpha pathway might play an important role in growth inhibition of pancreatic cancer cells via G1 cell cycle arrest and apoptosis [5].
• Full-length RXRalpha accumulated in leiomyomas was abnormally phosphorylated at serine/threonine residues relative to myometrial tissue [6].

High impact information on RXRA

• The X-ray crystal structure of the human constitutive androstane receptor (CAR, NR1I3)/retinoid X receptor alpha (RXRalpha, NR2B1) heterodimer sheds light on the mechanism of ligand-independent activation of transcription by nuclear receptors [7].
• As2O3 did not inhibit transactivation of the estrogen receptor or the glucocorticoid receptor, which do not heterodimerize with RXRalpha [8].
• We now report that As2O3 inhibits ligand-induced transcription of the retinoic acid receptor, as well as other nuclear receptors that heterodimerize with the retinoid X receptor alpha (RXRalpha) [8].
• Phosphorylation of RXRalpha has been reported to inhibit nuclear receptor signaling, and we show by in vivo labeling and phosphoamino acid detection that As2O3 phosphorylated RXRalpha in the N-terminal ABC region exclusively on serine residues [8].
• A mutational analysis indicated that phosphorylation of a specific serine residue, S32, was primarily responsible for inhibition of RXRalpha-mediated transcription [8].

Chemical compound and disease context of RXRA

• These results suggest that acyclic retinoid may act through both RXR alpha and RAR beta, whereas all-trans-RA conveys only RAR beta-mediated functions, at least in these two hepatoma cell lines [4].
• We examined the effects of troglitazone (one type of TZDs) and 9-cis retinoic acid, a RXRalpha ligand, on activation of PPARgamma/RXRalpha and growth inhibition of human pancreatic cancer cell lines (AsPC1, BxPC3, PSN1, PCI6, Panc1, KMP-4, and KMP-7) [5].
• We compared the effects of six types of TZDs (troglitazone, RS-1303, RS-1330, RS-1387, RS-1455, and RS-1456) and 9-cis RA, an RXRalpha ligand, on the activation of PPARgamma/RXRalpha and the growth inhibition of six types of adenocarcinoma cell lines (MKN45, HT-29, HCT116, HuCCT1, KMP-2, and BxPC3) established from abdominal malignancies [9].
• Ubiquitinated or sumoylated retinoic acid receptor alpha determines its characteristic and interacting model with retinoid X receptor alpha in gastric and breast cancer cells [10].

Biological context of RXRA

• A cosmid clone was isolated using the RXRA PCR product, and this was used to further localize the gene by fluorescence in situ hybridization to chromosome 9q34 distal to the dopamine beta hydroxylase gene (DBH) [11].
• The identification of RXR alpha as a dimerization partner for the RARs, T3Rs and VD3R has important implications as to the function of these receptors and their ligands in development, homeostasis and neoplasia [12].
• Mutated RXR alpha (S260A) inhibited 1,25D-induced CYP24 promoter activity and abolished phosphorylation by activated ERK2 [13].
• The retinoid antagonists also inhibited all-trans-RA-induced transcriptional activation of RARbeta/RXRalpha heterodimers, although they did not show any effect on transactivation activity of RXR/RXR homodimers [2].
• We concluded that two genomic DNA regions, the DR4 site (-1531 to -1516) and the first and second Sp1-binding sites (-145 to -121), were involved in the RA-dependent augmentation of thrombomodulin gene expression through increased interactions of the two regions with heterodimer of RAR-RXRalpha and nuclear Sp1, respectively [14].

Anatomical context of RXRA

• Localization of RXRA was achieved using the polymerase chain reaction on a panel of somatic cell hybrids [11].
• Arsenite decreases CYP3A4 and RXRalpha in primary human hepatocytes [15].
• Ubiquitin/proteasome pathway regulates levels of retinoic acid receptor gamma and retinoid X receptor alpha in human keratinocytes [16].
• In the present study, we have demonstrated that, unlike resting cells, activation of cycling human mature PBT lymphocytes, and T lymphocyte leukemia cell lines is accompanied by the accumulation of RXRalpha mRNA and protein [17].
• Transfection analysis in Jurkat cells, using RXRE-dependent reporter assays, showed that RXRalpha accumulated during T cell activation was transcriptionally inactive [17].

Associations of RXRA with chemical compounds

• RXR alpha, a promiscuous partner of retinoic acid and thyroid hormone receptors [12].
• Retinoid X receptor alpha (RXR alpha) is a member of the steroid hormone receptor superfamily [18].
• The two nuclear receptor-binding motifs within the PBREM effectively bound PXR as a heterodimer with the 9-cis retinoic acid receptor alpha (NR2B1) [19].
• The transactivation response requires the DNA binding domain and AF-2 motif of CAR3 and is markedly enhanced by retinoid X receptor-alpha (RXR) cotransfection [20].
• Accumulation of RXRalpha and PXR mRNA reaches a maximum at a concentration of 100 nM dexamethasone after treatment for 6 to 12 h and is greatly diminished by RU486 [21].
• This partial resistance to ligands could be reversed by inhibition of MAPK activity or by overexpression of a non-phosphorylable RXRalpha mutant at serine 260 (RXRalpha Ser-260-->Ala) [22].

Physical interactions of RXRA

• Immunoprecipitation experiments show that beta-catenin interacts with RXR-alpha and PPAR-gamma in some malignant cells [23].
• PELP1 was found to be a binding partner of RXRalpha, and the binding interactions were confirmed both in vitro and in vivo [24].
• Further, data is presented which show that high-affinity ligand binding to the RXRalpha ligand-binding domain (LBD) stabilises the domain homodimer [25].

Enzymatic interactions of RXRA

• Mitogen-activated protein kinase inhibits 1,25-dihydroxyvitamin D3-dependent signal transduction by phosphorylating human retinoid X receptor alpha [26].
• We present evidence that in neuroblastoma CHP126 cells, CAK interacts with and phosphorylates retinoblastoma tumor suppressor protein (pRb) and retinoid X receptor alpha (RXRalpha) [27].

Co-localisations of RXRA

• In COS7 cells, overexpressed RNF8 colocalized and interacted with RXR alpha in the nucleus, as shown by fluorescence resonance energy transfer [18].

Regulatory relationships of RXRA

• Northern analyses showed that RAR-alpha and RAR-beta were not significantly regulated, while RAR-gamma was up-regulated and retinoid X receptor alpha was down-regulated by 9-cis RA [28].
• Retinoic acid receptors and retinoid X receptor-alpha down-regulate the transforming growth factor-beta 1 promoter by antagonizing AP-1 activity [29].
• A shift in the ligand responsiveness of thyroid hormone receptor alpha induced by heterodimerization with retinoid X receptor alpha [30].
• These nucleotide substitutions prevent the binding of the retinoid X receptor alpha (RXR alpha)-peroxisome proliferator-activated receptor alpha (PPAR alpha) heterodimer without greatly altering the efficiency of binding of hepatocyte nuclear factor 4 (HNF4) to this recognition sequence [31].
• Two retinoic acid response elements (RAREs) to which retinoid X receptor alpha (RXRalpha) and retinoic acid receptor alpha (RARalpha) bind and activate transcription are present in the human PDK4 (hPDK4) proximal promoter [32].

Other interactions of RXRA

• The RING finger protein, RNF8, interacts with retinoid X receptor alpha and enhances its transcription-stimulating activity [18].
• Retinoid X receptor-alpha-dependent transactivation by a naturally occurring structural variant of human constitutive androstane receptor (NR1I3) [20].
• Transfection analysis in mammalian cells demonstrated that RIP140 antagonized PPARalpha/RXRalpha- and LXRalpha/RXRalpha-mediated signaling [33].
• FISH of a canine specific genomic cosmid clone for RXRA demonstrated the more telomeric localization of this locus to NF1 on CFA9 [34].
• These data demonstrate a dual regulatory control of RXRalpha expression during the activation of resting and cycling T lymphocytes and indicate a dynamic balance between JNK and ERK pathways in modulating RXRE-mediated transactivation [17].

Analytical, diagnostic and therapeutic context of RXRA

• Electrophoretic mobility shift assays confirmed that the ACE66 sequence was recognized as a high affinity target for binding of heterodimers of recombinant vitamin D receptor (VDR) and its partner, retinoid-X receptor-alpha (RXRalpha) [35].
• Electrophoretic mobility shift assay and chromatin immunoprecipitation assay experiments showed that the 2 cytochrome P450 1A1 peroxisome proliferator response element sites bind the peroxisome proliferator-activated receptor-alpha/retinoid X receptor-alpha heterodimer [36].
• The expression levels of human RAR alpha (hRAR alpha, receptor for all-trans RA) and the human retinoid-X receptor alpha (hRXR alpha receptor for 9-cis RA) were determined by Northern blot analysis [37].
• This finding was confirmed by double immunofluorescence labeling of RXRalpha and Keratin-903, a basal cell marker, followed by confocal microscopic examination [38].
• Immunohistochemistry with anti-RXRalpha antibody was performed on 138 fresh frozen prostate specimens collected from 27 noncarcinomatous prostates and 111 radical prostatectomy samples of prostate adenocarcinoma (CA) [38].

References