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)

All-trans retinoic acid (tRA) inhibits growth of estrogen receptor-positive (ER+) breast cancer cells in vitro, and a variety of retinoids inhibit development of breast cancer in animal models. 9-cis retinoic acid (9-cis RA) is a naturally occurring high affinity ligand for the retinoid X receptors, as well as the retinoic acid receptors (RARs). Whether 9-cis RA has a different spectrum of biological activity from tRA, which only binds RARs with high affinity, is largely unknown. We studied the effects of 9-cis RA on growth and gene expression in ER+ and ER- human breast cancer cells. 9-cis RA inhibited the growth in monolayer culture of several ER+, but not ER-, cell lines in a dose-dependent manner. Growth inhibition and morphological changes by 9-cis RA were similar to those of tRA, suggesting that the ability to bind both RAR and retinoid X receptors did not significantly augment growth inhibition or confer sensitivity to tRA-resistant lines. MCF-7 cells exposed to 9-cis RA showed a dose-dependent accumulation in G1. 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. Since interactions between tRA and ER-dependent transcription have recently been reported, we investigated whether these retinoids regulate expression of ER itself or estrogen-responsive genes. Both 9-cis RA and tRA induce down-regulation of ER mRNA and protein in MCF-7 cells. 9-cis RA down-regulates expression of the estrogen-responsive genes PR and pS2 in MCF-7 cells as reported previously for tRA. In several ER-positive subclones, we found that the degree of ER expression and regulation, but not always estrogen-sensitivity, correlates with the growth-inhibitory effects of 9-cis RA. Further, in an ER-, retinoid-unresponsive breast cancer cell line, induced ER expression confers responsiveness to retinoid growth inhibition. These data, combined with reports of additive growth inhibition of tRA and tamoxifen in vitro, suggest that 9-cis RA might augment the ability of tamoxifen to inhibit growth of ER+ breast cancer cells in vivo.
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PMID:9-Cis retinoic acid inhibits growth of breast cancer cells and down-regulates estrogen receptor RNA and protein. 798 55

Estrogen receptor (ER)-positive human breast cancer cells are hormonally regulated and are inhibited by retinoids, whereas most ER-negative breast cancer cells are not. Here, we compared retinoid-induced transcriptional activation and growth inhibition in the ER-negative breast cancer cell line MDA-MB-231, stably transfected to express wild-type ER (S30), with that of the ER-positive MCF-7 line and the ER-negative parental line. Retinoids inhibited growth of the ER-expressing S30 clone but not of the parental MDA-MB-231 cells. Unlike a previously reported MDA-MD-231 subclone that was transfected to express a mutated ER (G400V), S30 did not express increased levels of retinoid receptor RNA or protein, nor was there increased binding activity to retinoid-responsive DNA elements. However, stable expression of ER increased retinoid activation of transcription of a retinoic acid (RA) response elements from the low level in MDA-MB-231 to approach the level of MCF-7. The restored growth inhibition and transcriptional regulation by RA were unaffected by treatment with ER agonists or antagonists. Transient expression of ER but not of other nuclear receptors in MDA-MB-231 cells also activated retinoid-induced transcription, showing that this response is specific to ER. Furthermore, the effect of exogenously expressed ER on retinoid response was much greater than that obtained by overexpression of RA receptor alpha and/or retinoid X receptor alpha. Finally, a panel of ER mutants showed that enhancement of retinoid-induced transcriptional activity was dependent on the integrity of the DNA binding domain.
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PMID:Estrogen receptor expression activates the transcriptional and growth-inhibitory response to retinoids without enhanced retinoic acid receptor alpha expression. 982 20

Most studies have reported an up-regulation of retinoic acid receptor (RAR) mRNA expression by all-trans retinoic acid (RA). We aimed to study the effect of RA on RAR protein levels in MCF-7 human breast cancer cells. Incubation of these cells with 10(-6) M RA induced a rapid breakdown of both RARalpha and RARgamma in spite of the accumulation of their mRNAs. Proteasome specific inhibitors blocked the RA-induced breakdown of RARs. Furthermore, RA enhanced the formation of the complex between RARalpha and ubiquitin in a concentration- and time-dependent manner, suggesting the involvement of ubiquitin and proteasome in this reaction. Retinoid X receptor alpha (RXRalpha) was also decreased, albeit to a lesser extent, in RA-treated cells. Use of synthetic receptor agonists and antagonists clearly showed that the effect of the retinoid on the breakdown of the retinoid receptors is receptor-ligand agonist-dependent and blunted by the antagonist. An electrophoretic mobility shift assay, using nuclear extracts from RA-treated cells, showed that a reduction in complex formation with hormone response elements correlated with the reduction of RAR and RXR protein. These data suggest that RA induces the breakdown of RARs through a process involving ubiquitination and that this phenomenon causes a reduction in the formation of DNA-receptor complexes.
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PMID:Involvement of all-trans-retinoic acid in the breakdown of retinoic acid receptors alpha and gamma through proteasomes in MCF-7 human breast cancer cells. 1133 Oct 70

The retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic acid (AHPN) is reported to have anticancer activity in vivo. Induction of cell cycle arrest and apoptosis in cancer cell lines refractory to standard retinoids suggests a retinoid-independent mechanism of action for AHPN. Conformational studies suggested that binding of AHPN does not induce an unusual conformation in retinoic acid receptor (RAR) gamma. The 3-chloro AHPN analogue MM11453 inhibited the growth of both retinoid-resistant (HL-60R leukemia, MDA-MB-231 breast, and H292 lung) and retinoid-sensitive (MCF-7 breast, LNCaP prostate, and H460 lung) cancer cell lines by inducing apoptosis at similar concentrations. Before apoptosis, MM11453 induced transcription factor TR3 expression and loss of mitochondrial membrane potential characteristic of apoptosis. MM11453 lacked the ability to significantly activate RARs and retinoid X receptor alpha to initiate (TREpal)(2)-tk-CAT reporter transcription. These results, differential proteolysis-sensitivity assays, and glutathione S-transferase-pulldown experiments demonstrate that, unlike AHPN or the natural or standard synthetic retinoids, MM11453 does not behave as a RAR or retinoid X receptor alpha transcriptional agonist. These studies strongly suggest that AHPN exerts its cell cycle arrest and apoptotic activity by a signaling pathway independent of retinoid receptor activation.
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PMID:Apoptosis induction in cancer cells by a novel analogue of 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic acid lacking retinoid receptor transcriptional activation activity. 1140 43

To understand the mechanism of retinoid resistance, we studied the subcellular localization and function of retinoid receptors in human breast cancer cell lines. Retinoid X receptor alpha (RXR alpha) localized throughout the nucleoplasm in retinoid-sensitive normal human mammary epithelial cells and in retinoid-responsive breast cancer cell line (MCF-7), whereas it was found in the splicing factor compartment (SFC) of the retinoid-resistant MDA-MB-231 breast cancer cell line and in human breast carcinoma tissue. In MDA-MB-231 cells, RXR alpha was not associated with active transcription site in the presence of ligand. Similarly, ligand-dependent RXR homo- or heterodimer-mediated transactivation on RXR response element or RARE showed minimal response to ligand in MDA-MB-231 cells. Infecting MDA-MB-231 cells with adenoviral RXR alpha induced nucleoplasmic overexpression of RXR alpha and resulted in apoptosis upon treatment with an RXR ligand. This suggests that nucleoplasmic RXR alpha restores retinoid sensitivity. Epitope-tagged RXR alpha and a C-terminus deletion mutant failed to localize to the SFC. Moreover, RXR alpha localization to the SFC was inhibited with RXR alpha C-terminus peptide. This peptide also induced ligand-dependent transactivation on RXRE. Therefore, the RXR alpha C terminus may play a role in the intranuclear localization of RXR alpha. Our results provide evidence that altered localization of RXR alpha to the SFC may be an important factor for the loss of retinoid responsiveness in MDA-MB-231 breast cancer cells.
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PMID:Altered localization of retinoid X receptor alpha coincides with loss of retinoid responsiveness in human breast cancer MDA-MB-231 cells. 1508 90

Retinoic acid receptor alpha (RARalpha) plays an important role in mediating all-trans retinoic acid (ATRA) signals. In this study, we found that ATRA up-regulated RARalpha mRNA and protein expression in gastric cancer BGC-823 cells. However, in breast cancer MCF-7 cells it down-regulated RARalpha protein expression with no effect on its RARalpha mRNA. Immunoprecipitation/Western blot analysis showed that, although sumoylated and ubiquitinated RARalpha existed simultaneously in both cancer cell lines, ATRA exerted different regulatory effects on sumoylation and ubiquitination of RARalpha. In MCF-7 cells, ATRA treatment enhanced the ubiquitination of RARalpha and the subsequent degradation of RARalpha through the ubiquitin/proteasome pathway. This resulted in a reduction in the DNA binding activity of RARalpha/retinoid X receptor alpha (RXRalpha) heterodimer, the separation of RXRalpha from RARalpha and the translocation of RXRalpha from the nucleus to the cytoplasm. By contrast, in BGC-823 cells, ATRA augmented sumoylation, not ubiquitination, of RARalpha. The stability of sumoylated RARalpha was significantly stronger than in non-sumoylated RARalpha. These results also showed an increase in the DNA binding activity of the RARalpha/RXRalpha heterodimer and the stability of nuclear localization of this heterodimer, which normally facilitates the ATRA signal transduction. In conclusion, our results reveal a novel mechanism for the regulation of RARalpha-dependent signal transduction through the ubiquitin/proteasome pathway in breast cancer cells and the sumoylation pathway in gastric cancer cells.
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PMID:Ubiquitinated or sumoylated retinoic acid receptor alpha determines its characteristic and interacting model with retinoid X receptor alpha in gastric and breast cancer cells. 1517 3

Retinoid X receptor alpha (RXRalpha), functioning as either a homodimer or a heterodimer with peroxisome proliferator receptors, is known to be involved in manifesting antiproliferative effects in cells. Consequently, studies of RXRalpha functions and its coregulators have been in the focus for therapeutic approaches against cancer. Here we have discovered that 9-cis-retinoic acid (9-cis-RA), a RXRalpha-specific ligand, up-regulated the expression of transcriptional coregulatory protein PELP1 (proline-, glutamic acid-, and leucine-rich protein 1). PELP1 functioned as a coactivator of RXRalpha, increasing its transactivation function in response to 9-cis-RA as evident by the retinoid X receptor response element-luciferase assays. PELP1 was found to be a binding partner of RXRalpha, and the binding interactions were confirmed both in vitro and in vivo. An electrophoretic mobility shift assay showed greater formation and stability of RXRalpha homodimers on consensus oligonucleotides in PELP1-overexpressing clones in comparison to the pcDNA clones. The presence of PELP1 in these oligonucleotide-bound RXRalpha homodimers was proved by the supershift of the complex when incubated with PELP1-specific antibody. PELP1-overexpressing stable MCF-7 cells exhibited a significantly higher extent of 9-cis-RA-induced apoptosis than the control pcDNA clones. Silencing of PELP1 expression in parental MCF-7 cells and PELP1-overexpressing clones using PELP1-specific RNA-mediated interference compromised the susceptibility to 9-cis-RA-induced apoptosis. PELP1 could also function as a coactivator of the RXRalpha-peroxisome proliferator-activated receptor (PPARgamma) heterodimer as evident by the peroxisome proliferator-activated receptor response element-luciferase assay in response to both 9-cis-RA and PPARgamma-specific ligands. This was reinforced by the higher propensity of PELP1-overexpressing clones to undergo differentiation in response to PPARgamma-specific ligands. This study has revealed a novel facet of PELP1 functions and identified it to be an important potentiator of the antiproliferative effects of 9-cis-RA and PPARgamma-specific ligands.
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PMID:9-cis-retinoic acid up-regulates expression of transcriptional coregulator PELP1, a novel coactivator of the retinoid X receptor alpha pathway. 1657 51