Differential expression of the alpha and beta retinoic acid receptors in tissues of the rat.
Ontology highlight
ABSTRACT:
SUBMITTER: Rees JL
PROVIDER: S-EPMC1138606 | biostudies-other | 1989 May
REPOSITORIES: biostudies-other
Similar Datasets
Project description:Binding of retinoic acid (RA) to specific RA receptors alpha and beta (RAR alpha and RAR beta) was studied. Receptors were obtained in two ways: (1) full-length receptors were produced by transient expression of the respective human cDNAs in COS 1 cells; and (2) the ligand-binding domains of RAR alpha and RAR beta were produced in Escherichia coli. RA binding to the wild-type and truncated forms of the receptor was identical for both RAR alpha and RAR beta, indicating that the ligand-binding domains have retained the binding characteristics of the intact receptors. Furthermore, RA bound with the same affinity to both RAR alpha and RAR beta. Only retinoid analogues with an acidic end-group were able to actively bind to both receptors. On measuring the binding of various retinoids, we have found that the properties of the ligand-binding sites of RAR alpha and RAR beta were rather similar. Two retinoid analogues were capable of binding preferentially to either RAR alpha or RAR beta, suggesting that it may be possible to synthesize specific ligands for RAR alpha and RAR beta.
| S-EPMC1149712 | biostudies-other
Project description:We have investigated the effects of retinoids, vitamin D and thyroid hormone on the levels of retinoic acid receptor (RAR)alpha, RAR beta and RAR gamma mRNAs in intact animals. Although vitamin A deficiency caused no significant changes in the levels of RAR alpha and RAR gamma mRNAs, the level of RAR beta transcripts was greatly decreased in various tissues of vitamin A-deficient rats, but was restored rapidly to a normal level after administration of retinoic acid. Retinol also restored the RAR beta mRNA level, but the magnitude and kinetics of the induction differed from those by retinoic acid. The use of specific inhibitors demonstrated that this autoregulation of RAR beta gene expression in vivo occurred at the transcriptional level. In addition, from these results it was postulated that the maintenance of the normal RAR beta mRNA levels seemed to require a threshold serum retinol concentration (about 25 micrograms/dl). Moreover, we found that administration of retinol and retinoic acid to normal rats caused the overexpression of RAR beta transcripts (2-15-fold) when compared with the control levels of RAR beta mRNA, although the levels of RAR alpha and RAR gamma mRNAs were not affected. Vitamin D and thyroid hormone did not modulate the levels of RAR transcripts. These findings clearly indicate the specific ligand regulation of RAR beta gene expression in intact animals. The altered levels of RAR beta according to retinoid status may affect retinoid-inducible gene expression.
| S-EPMC1132968 | biostudies-other
Project description:Analysis of the sucrose-density-gradient patterns of the 110 000g supernatant fractions of adult and foetal retina and pigment epithelium showed them to contain a limited number of highly specific binding sites ('receptors') for [3H]retinoic acid that sediment at approx. 2S. Binding in pigment epithelium is higher than in any tissue yet reported. A 5S binding component is also observed and is probably due to serum contamination. Fractionation studies indicate that [3H]retinoic acid binding in the retina is lower in the photoreceptor units than in the retinal inner layers. This is in contrast with previous results that show greater [3H]retinol binding in photoreceptors. Studies with dystrophic human and rat retinas, which lack the photoreceptor layers, confirm that [3H]retinoic acid binding is greater in the non-photoreceptor layers of the retina. No specific [3H]retinoic acid binding is found in corneal epithelium, although endothelium and the conjunctiva demonstrate specific 2S binding. Such differences in retinol and retinoic acid binding may indicate different roles for the two compounds in ocular tissues.
| S-EPMC1184197 | biostudies-other
Project description:BACKGROUND:Folate receptor alpha (FOLR1/FRA) is expressed in a number of epithelial cancers and in particular epithelial ovarian cancer (EOC), especially of the serous histotype. Recent studies have shown that EOC originates from the fallopian tube fimbriae rather than from epithelial cells lining the ovary. We have previously shown by immunohistochemistry a strong correlation between FRA expression in EOC and normal and fallopian adenocarcinoma. Folate receptor beta (FOLR2/FRB) has been described to be expressed by macrophages both in inflammatory disorders and certain epithelial cancers. Given the high sequence identity of these two folate receptor family members we sought to investigate the architectural and cell-specific expression of these two receptors in gynecologic tissues. METHODS:RNA scope, a novel chromogenic in situ hybridization assay tool, was used to examine expression of the alpha (FOLR1) and beta (FOLR2) isoforms of folate receptor relative to each other as well as to the macrophage markers CD11b and CD68, in samples of normal fallopian tube and fallopian adenocarcinoma as well as normal ovary and EOC. RESULTS:We demonstrated expression of both FOLR1 and FOLR2 in EOC, normal fallopian tube and fallopian adenocarcinoma tissue while very little expression of either marker was observed in normal ovary. Furthermore, FOLR2 was shown to be expressed almost exclusively in macrophages, of both the M1 and M2 lineages, as determined by co-expression of CD11b and/or CD68, with little or no expression in epithelial cells. CONCLUSIONS:These findings further substantiate the hypothesis that the cell of origin of EOC is tubal epithelium and that the beta isoform of folate receptor is primarily restricted to macrophages. Further, macrophages expressing FOLR2 may represent tumor associated or infiltrating macrophages (TAMs) in epithelial cancers.
| S-EPMC4464638 | biostudies-literature
Project description:Considering the role of retinoids in regulation of more than 500 genes involved in cell cycle and growth arrest, a detailed understanding of the mechanism and its regulation is useful for therapy. The extract of the medicinal plant Neem (Azadirachta indica) is used against several ailments especially for anti-inflammatory, anti-itching, spermicidal, anticancer, and insecticidal activities. In this report we prove the detailed mechanism on the regulation of retinoic acid-mediated cell signaling by azadirachtin, active components of neem extract. Azadirachtin repressed all trans-retinoic acid (ATRA)-mediated nuclear transcription factor ?B (NF-?B) activation, not the DNA binding but the NF-?B-dependent gene expression. It did not inhibit I?B? degradation, I?B? kinase activity, or p65 phosphorylation and its nuclear translocation but inhibited NF-?B-dependent reporter gene expression. Azadirachtin inhibited TRAF6-mediated, but not TRAF2-mediated NF-?B activation. It inhibited ATRA-induced Sp1 and CREB (cAMP-response element-binding protein) DNA binding. Azadirachtin inhibited ATRA binding with retinoid receptors, which is supported by biochemical and in silico evidences. Azadirachtin showed strong interaction with retinoid receptors. It suppressed ATRA-mediated removal of retinoid receptors, bound with DNA by inhibiting ATRA binding to its receptors. Overall, our data suggest that azadirachtin interacts with retinoic acid receptors and suppresses ATRA binding, inhibits falling off the receptors, and activates transcription factors like CREB, Sp1, NF-?B, etc. Thus, azadirachtin exerts anti-inflammatory and anti-metastatic responses by a novel pathway that would be beneficial for further anti-inflammatory and anti-cancer therapies.
| S-EPMC3039373 | biostudies-literature
Project description:The liver X receptors α and β (LXRα and LXRβ) are oxysterol-activated transcription factors that coordinately regulate gene expression that is important for cholesterol and fatty acid metabolism. In addition to their roles in lipid metabolism, LXRs participate in the transcriptional regulation of macrophage activation and are considered potent regulators of inflammation. LXRs are highly similar, and despite notable exceptions, most of their reported functions are substantially overlapping. However, their individual genomic distribution and transcriptional capacities have not been characterized. Here, we report a macrophage cellular model expressing equivalent levels of tagged LXRs. Analysis of data from chromatin immunoprecipitation coupled with deep sequencing revealed that LXRα and LXRβ occupy both overlapping and exclusive genomic regulatory sites of target genes and also control the transcription of a receptor-exclusive set of genes. Analysis of genomic H3K27 acetylation and mRNA transcriptional changes in response to synthetic agonist or antagonist treatments revealed a putative mode of pharmacologically independent regulation of transcription. Integration of microarray and sequencing data enabled the description of three possible mechanisms of LXR transcriptional activation. Together, these results contribute to our understanding of the common and differential genomic actions of LXRs and their impact on biological processes in macrophages.
| S-EPMC6379585 | biostudies-literature
Project description:BACKGROUND:Nephroblastoma or Wilms tumor is the most frequent kidney cancer in children and accounts for 98% of kidney tumors in this age group. Despite favorable prognosis, a subgroup of these patients progresses to recurrence and death. The retinoic acid (RA) pathway plays a role in the chemoprevention and treatment of tumors due to its effects on cell differentiation and its antiproliferative, anti-oxidant, and pro-apoptotic activities. Reports describe abnormal cellular retinoic acid-binding protein 2 (CRABP2) expression in neoplasms and its correlation with prognostic factors and clinical and pathological characteristics. The aim of this study was to evaluate the immunohistochemical expression of retinoic acid receptor alpha (RARA) and CRABP2 in paraffin-embedded samples of nephroblastomas via semiquantitative and quantitative analyses and to correlate this expression with prognostic factors. METHODS:Seventy-seven cases of nephroblastomas were selected from pediatric oncology services. The respective medical records and surgical specimens were reviewed. Three representative tumor samples and one non-tumor renal tissue sample were selected for the preparation of tissue microarrays (TMA). The Allred scoring system was used for semiquantitative immunohistochemical analyses, whereas a morphometric analysis of the stained area was employed for quantitative evaluation. The nonparametric Mann-Whitney test was used for comparisons between two groups, while the nonparametric Kruskal-Wallis test was used to compare three or more groups. RESULTS:Immunopositivity for RARA and CRABP2 was observed in both the nucleus and cytoplasm. All histological components of the nephroblastoma (blastema, epithelium, and stroma) were positive for both markers. RARA, based on semiquantitative analyses, and CRABP2, bases on quantitative analyses, exhibited increased immunohistochemical expression in patients with metastasis, with p values of 0.0247 and 0.0128, respectively. These findings were similar to the results of the quantitative analysis of RARA expression, showing greater immunopositivity in tumor samples of patients subjected to pre-surgical chemotherapy. No significant correlation was found with the other variables studied, such as disease stage, anaplasia, risk group, histological type, nodal involvement, and clinical evolution. CONCLUSIONS:Semiquantitative and quantitative analyses of the markers RARA and CRABP2 indicate their potential as biomarkers for tumor progression and their participation in nephroblastoma tumorigenesis.
| S-EPMC6389245 | biostudies-literature
Project description:We identified two novel beta-defensin precursors, preproGBD-1 and preproGBD-2, in the tissues of a goat. Although the precursors were identical in 96.8% of their bases and 88.2% (60 of 68) of their amino acids, preproGBD-1 was expressed principally in the tongue and respiratory tract, whereas preproGBD-2 expression predominated throughout the intestine. These findings exemplify the phenomenon of tissue-specific expression in a family of host defense peptides that arose before the avian and mammalian lineages diverged.
| S-EPMC97022 | biostudies-literature
Project description:Vitamin A-derived metabolites act as ligands for nuclear receptors controlling the expression of a number of genes. Stereospecific saturation of the C(13)-C(14) double bond of all-trans-retinol by the enzyme, retinol saturase (RetSat), leads to the production of (R)-all-trans-13,14-dihydroretinol. In liver and adipose tissue, expression of RetSat is controlled by peroxisome proliferator-activated receptors (PPAR) alpha and gamma, respectively. Expression of RetSat in adipose tissue is also required for PPARgamma activation and adipocyte differentiation, but the involved mechanism is poorly understood. In this study, we examined the potential of (R)-all-trans-13,14-dihydroretinol and its metabolites to control gene transcription via nuclear receptors. Using a cell-based transactivation assay to screen 25 human nuclear receptors for activation, we found that dihydroretinoids have a narrow transcriptional profile limited primarily to activation of retinoic acid receptors (RARs). Although (R)-all-trans-13,14-dihydroretinoic acid exhibited comparable potency to retinoic acid in promoting the interaction of RARs with a coactivator peptide in vitro, its potency in activating RAR-controlled genes in cell-based assays was much lower than that of retinoic acid. As an explanation for the weak RAR agonist activity of dihydroretinoids in cell-based assays, we propose that both delivery of ligand to the nucleus and RAR activation favor retinoic acid over dihydroretinoids. Discrimination between the cognate ligand, retinoic acid, and close analogs such as dihydroretinoids, occurs at multiple levels and may represent a mechanism to modulate retinoid-dependent physiological processes.
| S-EPMC2784734 | biostudies-literature
Project description:Purinergic signaling has broad physiological significance to the hearing organ, involving signal transduction via ionotropic P2X receptors and metabotropic G-protein-coupled P2Y and P1 (adenosine), alongside conversion of nucleotides and nucleosides by ecto-nucleotidases and ecto-nucleoside diphosphokinase. In addition, ATP release is modulated by acoustic overstimulation or stress and involves feedback regulation. Many of these principal elements of the purinergic signaling complex have been well characterized in the cochlea, while the characterization of P2Y receptor expression is emerging. The present study used immunohistochemistry to evaluate the expression of five P2Y receptors, P2Y(1), P2Y(2), P2Y(4), P2Y(6), and P2Y(12), during development of the rat cochlea. Commencing in the late embryonic period, the P2Y receptors studied were found in the cells lining the cochlear partition, associated with establishment of the electrochemical environment which provides the driving force for sound transduction. In addition, early postnatal P2Y(2) and P2Y(4) protein expression in the greater epithelial ridge, part of the developing hearing organ, supports the view that initiation and regulation of spontaneous activity in the hair cells prior to hearing onset is mediated by purinergic signaling. Sub-cellular compartmentalization of P2Y receptor expression in sensory hair cells, and diversity of receptor expression in the spiral ganglion neurons and their satellite cells, indicates roles for P2Y receptor-mediated Ca(2+)-signaling in sound transduction and auditory neuron excitability. Overall, the dynamics of P2Y receptor expression during development of the cochlea complement the other elements of the purinergic signaling complex and reinforce the significance of extracellular nucleotide and nucleoside signaling to hearing.
| S-EPMC2912996 | biostudies-literature