Disease relevance of NR2C1

• TR2 orphan receptor functions as negative modulator for androgen receptor in prostate cancer cells PC-3 [1].
• The suppression of ER transcription by TR2 consequently caused the inhibition of estrogen-induced cell growth and G(1)/S transition in estrogen-dependent breast cancer cells [2].
• Additionally, one of the HPV-16 gene products, the E6 oncogene, regulates TR2 gene expression [3].
• The orphan nuclear receptor TR2 functions as a constitutive activator for the endogenous retinoic acid receptor beta2 (RAR(beta2)) gene expression in P19 embryonal carcinoma cells and for reporters driven by the RAR(beta2) promoter in COS-1 cells [4].
• Here we report that the testicular orphan receptor-2 (TR2) expression, which modulates many signal pathways, was completely repressed in the surgery-induced cryptorchidism of the rhesus monkey [5].

Psychiatry related information on NR2C1

• Waking after sleep onset increased from the second (TR2) to the third (TR3) trimester, whereas rapid eye movement (REM) sleep decreased from the first trimester (TR1) to TR2 [6].

High impact information on NR2C1

• Preligand assembly domain-mediated ligand-independent association between TRAIL receptor 4 (TR4) and TR2 regulates TRAIL-induced apoptosis [7].
• Here, we show that inhibition of TRAIL-induced apoptosis by TR4 critically depends on its association with TR2 via the NH(2)-terminal preligand assembly domain overlapping the first partial cysteine-rich domain of both receptors [7].
• Unlike TR2 orphan receptors, the TR4 orphan receptor appears to be predominantly located in granule cells of the hippocampus and the cerebellum, suggesting that it may play some role(s) in transcriptional regulation in these neurons [8].
• Suppression of estrogen receptor-mediated transcription and cell growth by interaction with TR2 orphan receptor [2].
• Taken together in addition to the potential roles in spermatogenesis and neurogenesis, our data provide a novel biological function of TR2 that may exert an important repressor in regulating ER activity in mammary glands [2].

Chemical compound and disease context of NR2C1

• RESULTS: Orphan nuclear receptor TR2 suppressed androgen-mediated transactivation in prostate cancer PC-3 cells, and over-expression of TR2 suppressed PSA expression [1].
• Together our data provide evidence for feedback regulation between TR2 and HPV-16, which represents a novel regulatory pathway involving a member of the steroid receptor superfamily and the HPV-16 DNA tumor virus [3].
• When clones of human colon cancer cells were assayed with antibodies against the TR2 mucin repeat or non-TR2 epitopes, differences in relative expression of MUC2 proteins suggested multiple immunoreactive forms [9].

Biological context of NR2C1

• BACKGROUND: We have reported that human TR2 orphan nuclear receptor (TR2) can modulate the transcriptional activity of the reporter gene containing an AGGTCA direct repeat-hormone response element [10].
• Previous evidence demonstrated that a 63bp DNA fragment, named the promoter activating cis-element (PACE), has been identified as a positive regulatory region in the 5' promoter region of the human TR2 gene [11].
• The amino acid sequence of this protein, called TR4 orphan receptor, is closely related to the previously identified TR2 orphan receptor [8].
• Multiple functions of the TR2-11 orphan receptor in modulating activation of two key cis-acting elements involved in the retinoic acid signal transduction system [12].
• TR2 can regulate several target genes via binding to a consensus response element (AGGTCA) in direct repeat orientation (AGGTCAX((n))AGGTCA, n = 0-6) [3].

Anatomical context of NR2C1

• OBJECTIVE: The aim of this study is to investigate the potential role and regulation of TR2 in human HaCaT keratinocytes [10].
• TR2 orphan receptor (TR2), a member of the nuclear receptor superfamily without identified ligands, is found to be expressed in the breast cancer cell lines and to function as a repressor to suppress ER-mediated transcriptional activity [2].
• In the developing testis, TR2 and TR4 are coexpressed in the same testicular cell populations and exhibit a parallel pattern of expression along development [13].
• Northern blot analysis has shown that TR2 mRNA is about 2.5 kilobases (kb) and is relatively abundant in androgen-sensitive organs, such as ventral prostate and seminal vesicle [14].
• These data indicate that LIGHT and TR2 expressed in macrophages are involved in the pathogenesis of RA by inducing the expression pro-inflammatory cytokines and matrix degrading enzymes [15].

Associations of NR2C1 with chemical compounds

• RESULTS: From CAT assays, TR2 can suppress retinoic acid (RA)-induced transactivation by 44.7% in HaCaT keratinocytes [10].
• The high homology between TR2 and TR4 orphan receptor suggests that these two orphan receptors constitute a unique subfamily within the steroid receptor superfamily [8].
• The dimerization is mediated by the ligand binding domains, and the three leucine residues on helix 10 of TR2 are critical for this interaction [13].
• This evidence suggests that TR2 mRNA levels are negatively controlled by androgen in the rat ventral prostate [14].
• Dot blot hybridization indicates that TR2 mRNA levels increased after castration of rats, and this increase is reversed by 5 alpha-dihydrotestosterone injection [14].

Physical interactions of NR2C1

• Identification of histone deacetylase-3 domains that interact with the orphan nuclear receptor TR2 [16].
• The orphan nuclear receptor TR2 interacts directly with histone deacetylase HDAC3 and HDAC4 [16].

Other interactions of NR2C1

• Differential and bi-directional regulation between TR2/TR4 orphan nuclear receptors and a specific ligand mediated-peroxisome proliferator-activated receptor alpha in human HaCaT keratinocytes [10].
• Sequence analysis of a 2.7-kb DNA fragment upstream of the TR2 orphan receptor translation start codon unveiled several potential cis-acting elements, such as AP-1, HNF-5, GATA1 binding sites, and GC boxes [17].
• Constitutive activation of retinoic acid receptor beta2 promoter by orphan nuclear receptor TR2 [4].

Analytical, diagnostic and therapeutic context of NR2C1

• Molecular cloning from neurulating Ambystoma mexicanum embryos of the cDNA encoding an orphan nuclear receptor (aDOR1) closely related to TR2-11 [18].
• The in vitro interaction between TR2 and TR4 is demonstrated by the yeast and the mammalian two-hybrid interaction assays, the pull-down assay, and the gel mobility shift assay [13].
• A direct molecular interaction occurs between CREMtau and TR2, detected by co-immunoprecipitation, which is mediated by the N-terminal AB segment of TR2 [4].
• The S1 nuclease protection assay for TR2 message revealed that there are multiple transcription initiations, and that the major cap site surrounded by an initiator-like sequence is located at the 104th nucleotide upstream from the translation start codon [17].
• With the screening of a human genomic library and the combination of primer walking and PCR sequencing, we found that the entire TR2 orphan receptor gene coding region and 5'-untranslated region feature 13 introns and 14 exons, and that the consensus splice sequences (GT-AG) are present in all intron-exon boundaries [17].

References