Disease relevance of RARG

• Potential role for retinoic acid receptor-gamma in the inhibition of breast cancer cells by selective retinoids and interferons [1].
• Cross-resistance to the synthetic retinoid CD437 in a paclitaxel-resistant human ovarian carcinoma cell line is independent of the overexpression of retinoic acid receptor-gamma [2].
• We have recently subcloned the D and E domains of human RAR gamma for expression in Escherichia coli [3].
• Implication of retinoic acid receptor gamma in squamous differentiation and response to retinoic acid in head and neck SqCC/Y1 squamous carcinoma cells [4].
• Overexpression of the retinoic acid receptor gamma directly induces terminal differentiation of human embryonal carcinoma cells [5].

High impact information on RARG

• All normal and premalignant specimens expressed similar levels of mRNA for retinoic acid receptor-alpha and retinoic acid receptor-gamma and the three types of retinoic X receptors, alpha, beta, and gamma [6].
• We report here that ultraviolet irradiation substantially reduced the mRNA and protein of the two major nuclear retinoid receptors, RAR-gamma and RXR-alpha, in human skin in vivo [7].
• CONCLUSIONS: These data suggest that the expression of RAR alpha, RXR alpha, and RXR gamma is not altered in NSCLC; however, expression of RAR beta and possibly also of RAR gamma and RXR beta is suppressed in a large percentage of patients with lung cancer [8].
• Phosphorylation by p38MAPK and recruitment of SUG-1 are required for RA-induced RAR gamma degradation and transactivation [9].
• Thus, the turnover of RAR gamma 2 is linked to transactivation [9].

Biological context of RARG

• We also mapped the three retinoic acid receptor genes in the mouse, by in situ hybridization, on chromosomes 11, band D (Rar-a); 14, band A (Rar-b); and 15, band F (Rar-g), respectively, and in the rat, using a panel of somatic cell hybrids that segregate rat chromosomes, on chromosomes 10 (RARA), 15 (RARB), and 7 (RARG), respectively [10].
• Based on a search for genes expressed late during nose formation and early in limb formation we identified retinoic acid receptor B (RARB) and retinoic acid receptor G (RARG) as possible candidate genes and sequenced bidirectionally including all exons and intron-exon bounders [11].
• This closed helix 12 conformation in RAR beta and RAR gamma blocks corepressor binding, prevents repression, and permits significant levels of target gene activation even in the absence of hormone [12].
• We present evidence that expression of the RAR gamma 2 isoform can be regulated through the RARE in its own promoter region [13].
• All seven cell lines expressed RAR-alpha and RAR-gamma, and four cell lines showed some changes by RA, but not associated with apoptosis [14].

Anatomical context of RARG

• To test this hypothesis in hematopoietic cells, we used retrovirus-mediated gene transduction to introduce the RA receptors RAR-alpha, RAR-beta, and RAR-gamma as well as RXR-alpha into a mutant subclone of the HL-60 promyelocytic leukemia cell line (designated HL-60R) that is relatively resistant to RA-induced granulocytic differentiation [15].
• The inhibitory effects of these analogues may be mediated by nuclear retinoic acid receptors as mRNA encoding RAR-alpha, RAR-gamma, and RXR-alpha were present, and RAR-beta was induced by RA in human lung fibroblasts [16].
• Unlike these two promoters, however, RAR gamma Bm382 did not inhibit transcription of the TREpal promoter in HeLa cells but did so in F9 cells [17].
• Ubiquitin/proteasome pathway regulates levels of retinoic acid receptor gamma and retinoid X receptor alpha in human keratinocytes [18].
• Cells cultured from four oral leukoplakia lesions were also examined and found to express RAR beta mRNA at relatively normal levels, but they expressed RAR gamma message at half the level of epithelial cells cultured from normal tissue [19].

Associations of RARG with chemical compounds

• RXR alpha and RAR alpha enhanced growth inhibition by all-trans-retinoic acid or 9-cis-retinoic acid, whereas RAR gamma was less effective, and RAR beta was ineffective [20].
• These studies indicate that of the retinoid receptors expressed in RA-treated NT2/D1 cells, it is the upregulation of RAR gamma that specifically induces the terminal differentiation of these cells [5].
• In comparison with the steroid receptor subfamily, various splice sites of RAR gamma occur at altered positions, suggesting that the RAR subfamily has diverged early during evolution [21].
• However, the response element is bound with high affinity by both RAR beta and RAR gamma as well as by thyroid hormone receptors [22].
• Interestingly, RAR-beta (SNU-80 and SNU-373) and RAR-gamma (SNU-790) was up-regulated by all-trans-retinoic acid treatment [23].

Physical interactions of RARG

• This RAR-binding activity represented in part the expression of RAR alpha and RAR gamma genes, whose transcripts were expressed in similar abundance in undifferentiated NHEK [24].
• A common ligand-binding pocket, involving predominantly hydrophobic residues, is inferred by homology modelling of the human RXR alpha and glucocorticoid receptor ligand-binding sites according to the RAR gamma holo-LBD structure [25].

Regulatory relationships of RARG

• 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 [26].
• All the cell lines expressed RAR-alpha mRNA and one cell line additionally expressed RAR-gamma mRNA [27].
• Intriguingly, both tRAR gamma and RAR gamma suppress keratin promoter activity in epidermal cells, although for tRAR gamma, the effect is mediated through the A/B domain whereas for RAR gamma, the effects require DNA binding [28].
• These data strongly suggest that the EGFR promoter is regulated by RAR-gamma, which itself is under the control of RA [29].
• In all cases, this agonist-induced conformational change promoted the direct association of retinoic acid receptor gamma with the transcriptional co-activator p300 and inhibited interaction of the receptor with the nuclear receptor co-repressor [30].

Other interactions of RARG

• As a consequence, the RAR beta and RAR gamma receptors appear to adopt a constitutively closed helix 12 conformation in the absence of hormone that may approximate the conformation of RAR alpha when bound to hormone agonist [12].
• These results suggest that RARgamma mediates the effects of RA on the cell growth both in monolayer culture and in semisolid medium possibly through AP-1 suppression [4].
• Thus, altered expression of CRABP-II appears more likely to regulate the cutaneous actions of RA than does altered expression of CRABP-I, RXR, or RAR-gamma isoforms [31].
• In contrast to RA (which activates RA receptors (RARs) and retinoid X receptors in HL-60 cells with its metabolite retinoids), a retinoid that selectively binds RAR-gamma, which is not expressed in HL-60 cells, was relatively ineffective in causing ERK2 activation [32].
• Furthermore, RARgamma and RXRalpha were polyubiquitinated in intact cells [18].

Analytical, diagnostic and therapeutic context of RARG

• Pulsed-field gel electrophoresis (PFGE) with RAR gamma probes demonstrated an Mlu-I restriction fragment length polymorphism, but no other structural abnormalities in these cells or a panel of germ cell tumor (GCT) cell lines [33].
• In this report, we describe the molecular cloning and characterization of one of the zebrafish RARs that is the predominant receptor in the regenerating caudal fin and corresponds most closely to the RAR-gamma subtype isolated from mouse and human and to RAR-delta from newt [34].
• In vitro growth activity was determined by using a colorimetric cell viability assay and analysis of cell cycle distribution, and apoptosis was performed by flow cytometry of propidium iodide-stained or fluorescent Annexin V-labeled cells, respectively, whereas expression of RAR-alpha and RAR-gamma was determined by Northern blotting [35].
• In this study, we determined the expression of RAR alpha, RAR beta, RAR gamma, and RXR alpha by real-time PCR in four cell lines and in blast cells from patients with non-M3 AML before and after ATRA incubation [36].
• Gel shift analysis of known retinoic acid response elements (RAREs) in the RAR beta and RAR gamma genes demonstrates that the upregulation of these by genes by RA involves increased binding of complexes to the individual RAREs [37].

References