Disease relevance of RARB

• Furthermore, growth inhibition of esophageal cancer cell lines by all-trans retinoic acid has been associated with the constitutive and induced expression of RARB [1].
• Nuclear run-on assays and transient transfections with RAR beta 2 promoter constructs indicate the presence of trans-acting transcriptional defects in most lung cancer cell lines, which map to the RA response element (RARE) [2].
• All-trans-retinoic acid or the combination of ciglitazone and SR11237 was able to induce RAR beta in all-trans-retinoic acid-resistant MDA-MB-231 breast cancer cells only when the orphan receptor chick ovalbumin upstream promoter transcription factor was expressed, or in the presence of the histone deacetylase inhibitor trichostatin A [3].
• Previous work has shown that loss of expression of retinoic acid receptor beta is one of the most consistent molecular changes during oral cancer progression in vivo [4].
• Using NTera2/clone D1 (NT2/D1) human embryonal carcinoma cells as a model, we report that the RA induced terminal differentiation of these cells into a neuronal phenotype is characterized by an increase in expression of RAR alpha, RAR beta, RAR gamma, and a slight induction of RXR alpha [5].
• These results show that HDACi regulate expression of the tumor suppressor gene RARbeta by both transcriptional and posttranscriptional mechanisms and might then modulate sensitivity to the retinoid in neuroblastoma cells [6].

High impact information on RARB

• Suppression of retinoic acid receptor-beta in premalignant oral lesions and its up-regulation by isotretinoin [7].
• The expression of retinoic acid receptor-beta mRNA is selectively lost in premalignant oral lesions and can be restored by treatment with isotretinoin [7].
• We propose a model for transcriptional regulation of the RAR beta 2 promoter in EC cells in which RAR, following activation by RA, functionally interacts with hTFIID via an E1A-like activity present in EC cells [8].
• In embryonal carcinoma (EC) cells retinoic acid (RA) strongly induces transcription from the RA receptor beta 2 (RAR beta 2) promoter through an RA response element (RARE) located in close proximity to the TATA box [8].
• In contrast, all-trans and 9-cis RA have identical effects on induction of RAR beta 2 transcripts [9].

Chemical compound and disease context of RARB

• Expression and up-regulation of retinoic acid receptor-beta is associated with retinoid sensitivity and colony formation in esophageal cancer cell lines [10].
• Ciglitazone, but not 15d-PGJ(2), strongly induced RAR beta expression in human breast and lung cancer cell lines when used together with SR11237 [3].
• A retinoic acid receptor beta/gamma-selective prodrug (tazarotene) plus a retinoid X receptor ligand induces extracellular signal-regulated kinase activation, retinoblastoma hypophosphorylation, G0 arrest, and cell differentiation [11].
• Expression of retinoic acid receptor beta in human renal cell carcinomas correlates with sensitivity to the antiproliferative effects of 13-cis-retinoic acid [12].
• Reversal of DNA hypermethylation and reactivation of RARbeta by genistein were also observed in KYSE 150 cells and prostate cancer LNCaP and PC3 cells [13].
• In normal mammary epithelial cells and T47D breast cancer cells, small interfering RNA-mediated knockdown of all RXR isoforms or RARbeta, but not RARalpha or RARgamma alone, blocked the induction of IGFBP-6 by bexarotene [14].

Biological context of RARB

• We therefore assessed LOH on chromosome arm 3p and RARB expression in esophageal cancer to investigate the mechanism of altered RARB expression during carcinogenesis [1].
• They also establish or confirm and extend the following homologies: (i) between human chromosome 17, mouse chromosome 11, and rat chromosome 10 (RARA); (ii) between human chromosome 3, mouse chromosome 14, and rat chromosome 15 (RARB); and (iii) between human chromosome 12, mouse chromosome 15, and rat chromosome 7 (RARG) [15].
• Methylation of RARB also occurred more frequently in stage III as compared to stage II disease (odds ratio, 3.2; 95% CI, 1.1-8.8; P=0.03) [16].
• The discovery of two human nuclear receptors for RA (hRAR alpha and hRAR beta) acting as transcriptional RA-inducible enhancer factors has provided a basis for understanding how RA controls gene expression [17].
• Their amino-acid sequences are much more homologous to those of hRAR alpha and hRAR beta, respectively, than to each other, which suggests strongly that RAR alpha- and beta-subtypes have different functions [17].

Anatomical context of RARB

• Retinoic acid receptor beta and telomerase catalytic subunit expression in bronchial epithelium of heavy smokers [18].
• One of the earliest events following the exposure of bronchial epithelial cells to RA is the strong induction of RA receptor beta (RAR beta) mRNA [2].
• Interestingly, LE550 induced AP-1 activity when RARbeta and RXRalpha were expressed in HeLa cells but not in breast cancer cells [19].
• These studies demonstrate a selective up-regulation of RAR beta, in response to RA, in fibroblasts that manifest a decreased proliferative capacity [20].
• In 7 normal urothelium samples and 17 normal urine controls, no aberrant methylation was detected except for RARbeta methylation in 3 normal urothelium samples (42.9%) and 4 normal urine samples (23.5%), respectively [21].

Associations of RARB with chemical compounds

• Gel shift analysis indicated that PPAR gamma, in the presence of RXR, formed a strong complex with a retinoic acid response element (beta retinoic acid response element) in the RAR beta promoter [3].
• The induction of RAR beta expression by the ciglitazone and SR11237 combination was diminished by a PPAR gamma-selective antagonist, bisphenol A diglycidyl ether [3].
• 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 [19].
• Modeling the amino acid sequence in this region as an alpha-helical structure indicates that this tryptophan is adjacent to alanine 234, which corresponds to alanine 225 in RAR beta that has previously been linked to the ligand binding site [22].
• However, the response element is bound with high affinity by both RAR beta and RAR gamma as well as by thyroid hormone receptors [23].

Physical interactions of RARB

• RARbeta ligand-binding domain bound to an SRC-1 co-activator peptide: purification, crystallization and preliminary X-ray diffraction analysis [24].
• RAR alpha strongly interacts with SMRT and can repress target gene transcription, whereas RAR beta and -gamma interact with SMRT only weakly and fail to repress [25].
• Nuclear extracts prepared from COS-1 cells transfected with an expression vector for the nuclear RA receptors RAR alpha or RAR beta were enriched (20- to 100-fold) with a RA-binding activity that coeluted by size-exclusion HPLC with the putative RAR from HL-60 cells [26].
• By mutation analysis, we demonstrate that the effect of COUP-TF requires its binding to a DR-8 element present in the RARbeta promoter [27].
• Overexpressed BTG2 increases PRMT1 participation in the RARalpha protein complex on the RARbeta promoter, a target gene model, and enhances gene-specific histone H4 arginine methylation [28].

Regulatory relationships of RARB

• RAR-alpha was expressed but RAR-beta was not expressed in the three cell lines, and RAR-gamma was not expressed in SNU-790 [29].
• Induction of retinoic acid receptor-beta suppresses cyclooxygenase-2 expression in esophageal cancer cells [30].
• These findings suggest that histone acetylation mediated by histone acetyltransferase and p300 / CBP may play a role in the growth arrest and apoptosis induced by RARbeta transfection in oral squamous cell carcinoma [31].
• Retinoic acid receptor beta induces terminal differentiation of squamous cell carcinoma lines in the absence of cyclin-dependent kinase inhibitor expression [32].
• All-trans-retinoic acid treatment inhibits the growth of retinoic acid receptor beta messenger ribonucleic acid expressing thyroid cancer cell lines but does not reinduce the expression of thyroid-specific genes [33].

Other interactions of RARB

• Other 3p genes coding for receptor proteins THRB and RARB, are unlikely candidates for tumor suppression [34].
• TM mRNA levels were regulated by transcriptional activation via a retinoid receptor beta (RARbeta) [35].
• In contrast, CD38 expression was not inducible by ATRA in HL-60R cells, transfected with a functional RAR beta, RAR gamma, or RXR alpha receptor [36].
• In this report we demonstrate, using a novel panel of primary cultures of oral lesions, that loss of retinoic acid receptor beta expression at the dysplasia stage occurs during the transition from senescent to immortal phenotype but may occur independently to the loss of CDKN2A/p16 expression [4].
• Regulation of retinoic acid receptor beta expression by peroxisome proliferator-activated receptor gamma ligands in cancer cells [3].

Analytical, diagnostic and therapeutic context of RARB

• The re-expression of RARbeta and hMLH1 proteins by EGCG was demonstrated by Western blot [37].
• Northern blotting analysis demonstrated that the expression of RAR-gamma was 7-fold higher in the 2008/13/4 and 2008/17/4 cells than in the 2008 cells, whereas the expression of RAR-alpha and RAR-beta was not observed in any cell line [38].
• RAR-beta gene status could be derived from corresponding allelotyping and immunohistochemistry data [39].
• RAR beta mRNA expression is repressed before and after RA-treatment and is only detected using a reverse transcription polymerase chain reaction (RT-PCR) assay [40].
• Amplification of cDNA using PCR and RAR-beta isoform-specific primer pairs revealed that only SK-RC-06 cells expressed the RAR-beta1 isoform [12].

References