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Gene Review

NR2C2  -  nuclear receptor subfamily 2, group C,...

Homo sapiens

Synonyms: Nuclear receptor subfamily 2 group C member 2, Orphan nuclear receptor TAK1, Orphan nuclear receptor TR4, TAK1, TR2R1, ...
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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


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


Associations of NR2C2 with chemical compounds


Physical interactions of NR2C2


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


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].


  1. Convergence of two repressors through heterodimer formation of androgen receptor and testicular orphan receptor-4: a unique signaling pathway in the steroid receptor superfamily. Lee, Y.F., Shyr, C.R., Thin, T.H., Lin, W.J., Chang, C. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  2. Modulation of estrogen receptor-mediated transactivation by orphan receptor TR4 in MCF-7 cells. Shyr, C.R., Hu, Y.C., Kim, E., Chang, C. J. Biol. Chem. (2002) [Pubmed]
  3. An embryonic/fetal beta-type globin gene repressor contains a nuclear receptor TR2/TR4 heterodimer. Tanabe, O., Katsuoka, F., Campbell, A.D., Song, W., Yamamoto, M., Tanimoto, K., Engel, J.D. EMBO J. (2002) [Pubmed]
  4. Suppression of hepatitis B virus core promoter by the nuclear orphan receptor TR4. Lin, W.J., Li, J., Lee, Y.F., Yeh, S.D., Altuwaijri, S., Ou, J.H., Chang, C. J. Biol. Chem. (2003) [Pubmed]
  5. TAK1 downregulation reduces IL-1beta induced expression of MMP13, MMP1 and TNF-alpha. Klatt, A.R., Klinger, G., Neumüller, O., Eidenmüller, B., Wagner, I., Achenbach, T., Aigner, T., Bartnik, E. Biomed. Pharmacother. (2006) [Pubmed]
  6. Preligand assembly domain-mediated ligand-independent association between TRAIL receptor 4 (TR4) and TR2 regulates TRAIL-induced apoptosis. Clancy, L., Mruk, K., Archer, K., Woelfel, M., Mongkolsapaya, J., Screaton, G., Lenardo, M.J., Chan, F.K. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  7. Human and rat TR4 orphan receptors specify a subclass of the steroid receptor superfamily. Chang, C., Da Silva, S.L., Ideta, R., Lee, Y., Yeh, S., Burbach, J.P. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  8. Nemo-like kinase (NLK) acts downstream of Notch/Delta signalling to downregulate TCF during mesoderm induction in the sea urchin embryo. R??ttinger, E., Croce, J., Lhomond, G., Besnardeau, L., Gache, C., Lepage, T. Development (2006) [Pubmed]
  9. Negative feedback control of the retinoid-retinoic acid/retinoid X receptor pathway by the human TR4 orphan receptor, a member of the steroid receptor superfamily. Lee, Y.F., Young, W.J., Burbach, J.P., Chang, C. J. Biol. Chem. (1998) [Pubmed]
  10. 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. Inui, S., Lee, Y.F., Chang, E., Shyr, C.R., Chang, C. J. Dermatol. Sci. (2003) [Pubmed]
  11. A novel nuclear receptor heterodimerization pathway mediated by orphan receptors TR2 and TR4. Lee, C.H., Chinpaisal, C., Wei, L.N. J. Biol. Chem. (1998) [Pubmed]
  12. Blockade of transforming growth factor-{beta}-activated kinase 1 activity enhances TRAIL-induced apoptosis through activation of a caspase cascade. Choo, M.K., Kawasaki, N., Singhirunnusorn, P., Koizumi, K., Sato, S., Akira, S., Saiki, I., Sakurai, H. Mol. Cancer Ther. (2006) [Pubmed]
  13. Disruption of TR4 orphan nuclear receptor reduces the expression of liver apolipoprotein E/C-I/C-II gene cluster. Kim, E., Xie, S., Yeh, S.D., Lee, Y.F., Collins, L.L., Hu, Y.C., Shyr, C.R., Mu, X.M., Liu, N.C., Chen, Y.T., Wang, P.H., Chang, C. J. Biol. Chem. (2003) [Pubmed]
  14. Protein Phosphatase 6 Down-regulates TAK1 Kinase Activation in the IL-1 Signaling Pathway. Kajino, T., Ren, H., Iemura, S., Natsume, T., Stefansson, B., Brautigan, D.L., Matsumoto, K., Ninomiya-Tsuji, J. J. Biol. Chem. (2006) [Pubmed]
  15. Identification of direct repeat 4 as a positive regulatory element for the human TR4 orphan receptor. A modulator for the thyroid hormone target genes. Lee, Y.F., Pan, H.J., Burbach, J.P., Morkin, E., Chang, C. J. Biol. Chem. (1997) [Pubmed]
  16. Differential regulation of direct repeat 3 vitamin D3 and direct repeat 4 thyroid hormone signaling pathways by the human TR4 orphan receptor. Lee, Y.F., Young, W.J., Lin, W.J., Shyr, C.R., Chang, C. J. Biol. Chem. (1999) [Pubmed]
  17. Identification of a novel testicular orphan receptor-4 (TR4)-associated protein as repressor for the selective suppression of TR4-mediated transactivation. Yang, Y., Wang, X., Dong, T., Kim, E., Lin, W.J., Chang, C. J. Biol. Chem. (2003) [Pubmed]
  18. Nuclear orphan receptors regulate transcription of the gene for the human luteinizing hormone receptor. Zhang, Y., Dufau, M.L. J. Biol. Chem. (2000) [Pubmed]
  19. TIP27: a novel repressor of the nuclear orphan receptor TAK1/TR4. Nakajima, T., Fujino, S., Nakanishi, G., Kim, Y.S., Jetten, A.M. Nucleic Acids Res. (2004) [Pubmed]
  20. Cloning of rabbit TR4 and its bone cell-specific activity to suppress estrogen receptor-mediated transactivation. Harada, H., Kuboi, Y., Miki, R., Honda, C., Masushige, S., Nakatsuka, M., Koga, Y., Kato, S. Endocrinology (1998) [Pubmed]
  21. New variants of the human and rat nuclear hormone receptor, TR4: expression and chromosomal localization of the human gene. Yoshikawa, T., DuPont, B.R., Leach, R.J., Detera-Wadleigh, S.D. Genomics (1996) [Pubmed]
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