Disease relevance of NR2C2

• Together, these data demonstrate that the coupling of two different receptors, through the heterodimerization of AR and TR4, is a unique signaling pathway in the steroid receptor superfamily, which may facilitate further understanding of the complicated androgen action in prostate cancer or libido [1].
• Together, our results showing that TR4 can suppress ER function via protein-protein interaction not only represent a unique cross-talk signaling pathway in the nuclear receptor superfamily, it may also provide us with a new strategy to modulate ER function in the breast cancer cells [2].
• These data suggest that TR2/TR4 forms the core of a larger DRED complex that represses embryonic and fetal globin transcription in definitive erythroid cells, and therefore that inhibition of its activity might be an attractive intervention point for treating sickle cell anemia [3].
• Here we report a functional study of TR4 interaction with the core promoter of the hepatitis B virus (HBV) [4].
• The paper provides evidence that transforming growth factor-beta activated kinase 1 (TAK1, MEKK7), a downstream mediator of IL-1beta signal transduction, plays an important role in the regulation of catabolic events and inflammatory processes in the context of degenerative joint diseases [5].

High impact information on NR2C2

• TR2 and TR4 form a heterodimer that binds to the epsilon and gamma promoter DR1 sites [3].
• 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 [6].
• 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 [7].
• Human and rat TR4 orphan receptors specify a subclass of the steroid receptor superfamily [7].
• NLK function was found to be redundant with that of the MAP kinase ERK during mesoderm formation and to require the activity of the activating kinase TAK1 [8].

Chemical compound and disease context of NR2C2

• Furthermore, treatment of F9 murine teratocarcinoma (F9) cells with 10(-6) M all-trans-retinoic acid increased TR4 mRNA levels, and this change was accompanied by an increased amount of endogenous TR4 protein that can bind to RXRE in electrophoretic mobility shift assay [9].

Biological context of NR2C2

• This suppression is similar to our previous report showing TR4 orphan nuclear receptor (TR4) can suppress RA-induced transactivation [10].
• TR4 functions as a transcriptional modulator that controls various target genes via binding to the DNA hormone response elements [2].
• The human testicular orphan receptor 4 (TR4) is a member of the nuclear receptor superfamily that shows a broad tissue distribution with higher expression in the nervous system and male reproductive tract [2].
• The amino acid sequence of this protein, called TR4 orphan receptor, is closely related to the previously identified TR2 orphan receptor [7].
• The electrophoretic mobility shift assay shows that TR4 can bind to the direct repeat 1 sequence element (AGGTTAAAGGTCT, nucleotide coordinates 1757-1769, TR4RE-HBV) on the HBV core promoter [4].

Anatomical context of NR2C2

• 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].
• In the developing testis, TR2 and TR4 are coexpressed in the same testicular cell populations and exhibit a parallel pattern of expression along development [11].
• In contrast, TAK1-deficient mouse embryonic fibroblasts are resistant to TRAIL-induced apoptosis, and treatment of control mouse embryonic fibroblasts with 5Z-7-oxozeaenol did not drastically promote the TRAIL-induced activation of a caspase cascade [12].
• Together our data show that loss of TR4 down-regulates expression of the apoE/C-I/C-II gene cluster in liver cells, demonstrating important roles of TR4 in the modulation of lipoprotein metabolism [13].
• Amino acid sequence analysis indicates that the human TR4 orphan receptor (TR4) is a member of the estrogen/thyroid receptor subfamily of the steroid/thyroid receptor superfamily and recognizes the AGGTCA direct repeat (DR) of the hormone response element [9].

Associations of NR2C2 with chemical compounds

• TAK1 (transforming growth factor beta-activated kinase 1) is a serine/threonine kinase that is a mitogen-activated protein kinase kinase kinase and an essential intracellular signaling component in inflammatory signaling pathways [14].
• Our data therefore strongly suggest that the retinoid signal pathway can be regulated by TR4 in a negative feedback control mechanism, which may restrict retinoic acid signaling to certain elements in a cell-specific fashion [9].
• Identification of direct repeat 4 as a positive regulatory element for the human TR4 orphan receptor. A modulator for the thyroid hormone target genes [15].
• A reporter gene assay using chloramphenicol acetyltransferase demonstrated that TR4 repressed RA-induced transactivation in a TR4 dose-dependent manner [9].
• In situ hybridization analysis demonstrated that abundant testicular orphan receptor (TR4) transcripts were detected in kidney, intestine, and bone, which are vitamin D3 target organs [16].

Physical interactions of NR2C2

• Mammalian two-hybrid system and co-immunoprecipitation assays both demonstrate that TRA16 can interact strongly with TR4 [17].

Regulatory relationships of NR2C2

• These unique suppression mechanisms suggest that TRA16 may function as a novel repressor to selectively suppress the TR4-mediated transactivation [17].
• Here we report that instead of direct binding to hormone response elements for gene regulation, TR4 can also go through direct protein-protein interaction to repress estrogen receptor (ER)-mediated transactivation [2].
• Conversely, TR4 activated the hLHR promoter activity up to 2.5-fold through binding to the same cis-element [18].

Other interactions of NR2C2

• Modulation of estrogen receptor-mediated transactivation by orphan receptor TR4 in MCF-7 cells [2].
• TIP27: a novel repressor of the nuclear orphan receptor TAK1/TR4 [19].

Analytical, diagnostic and therapeutic context of NR2C2

• DRED is a 540 kDa complex; sequence determination showed that it contains the nuclear orphan receptors TR2 and TR4 [3].
• Further dissection of this repressive mechanism indicates that TR4 may suppress the HBV core promoter activity via repressing HNF4alpha-mediated transactivation by protein-protein interactions without inhibition of HNF4alpha DNA binding [4].
• RT-PCR analysis, using pairs of primers specific for each TR4, showed that both types of receptor express in various tissues [20].
• By fluorescence in situ hybridization, we have mapped the hTR4 gene to 3p25, a region deleted in some forms of cancer [21].
• Flow cytometry showed that the binding of Annexin V to cell surface was also synergistically increased by TRAIL in combination with TAK1 siRNA [12].

References