Alternative titles; symbols
HGNC Approved Gene Symbol: NR2C2
Cytogenetic location: 3p25.1 Genomic coordinates (GRCh38): 3:14,947,583-15,049,273 (from NCBI)
Members of the nuclear hormone receptor family, such as NR2C2, act as ligand-activated transcription factors. The proteins have an N-terminal transactivation domain, a central DNA-binding domain with 2 zinc fingers, and a ligand-binding domain at the C terminus. The activated receptor/ligand complex is translocated to the nucleus where it binds to hormone response elements of target genes (Yoshikawa et al., 1996).
Chang et al. (1994) cloned NR2C2, or TR4, a member of the nuclear hormone receptor superfamily, using degenerate PCR on RNA from the supraoptic nucleus of the brain with primers based on the conserved DNA-binding domain of these genes. They isolated TR4 cDNAs from both human and rat libraries. The cDNAs encode a predicted 615-amino acid human protein and a 596-amino acid rat protein that are 98% identical. The TR4 sequence is similar to that of the TR2 orphan receptor (Chang et al., 1994). Together they appear to form a distinct subfamily.
Hirose et al. (1994) cloned the TR4 gene, which they designated TAK1, from a human lymphoblastoma cDNA library. They stated that the predicted protein is 596 amino acids long. On SDS-PAGE, TR4 migrated as a 65-kD protein. Using Northern blot analysis, Hirose et al. (1994) found that TR4 is expressed as a 9.4-kb mRNA in many tissues, and as a 2.8-kb mRNA primarily in testis. The 2 transcripts appeared to differ in the length of the 3-prime untranslated region. In mouse and rat testis, TR4 was expressed most abundantly in spermatocytes.
Yoshikawa et al. (1996) used RT-PCR to show that in rat and human, 2 isoforms (with and without a 19 codon exon) could be detected; in human, they were both expressed widely in tissues including brain, placenta, and ovary. However, in the PA1 human ovarian cancer cell line only the short form was detected. The difference in cDNA length is a consequence of alternative splicing.
Nakajima et al. (2004) stated that TAK1 binds as a homodimer to direct repeats of the consensus sequence AGGTCA. They identified TIP27 (JAZF1; 606246) as a repressor of TAK1 transcriptional activity. Yeast and mammalian 2-hybrid analyses revealed that TIP27 interacted with TAK1, but not with other nuclear receptors, either in the presence or absence of their respective ligands. Protein pull-down and immunoprecipitation analyses confirmed the interaction between TAK1 and TIP27. Deletion analysis revealed that an N-terminal domain of TIP27 interacted with a portion of the ligand-binding domain of TAK1. Reporter gene assays showed that TIP27 repressed TIP1 transcriptional activity in a dose-dependent manner. TIP27 did not interfere with TIP1 homodimerization or with binding of TIP1 to DNA, suggesting that interaction of TIP27 with TAK1 may inhibit recruitment of a coactivator.
Yoshikawa et al. (1996) mapped the human NR2C2 gene to chromosome 3 using a somatic cell hybrid panel and refined the localization to 3p25 by fluorescence in situ hybridization.
Collins et al. (2004) found that Nr2c2-null mice were born at lower than mendelian ratios, with a significantly lower proportion of female than male knockout mice. A growth defect was apparent early in postnatal life in affected mice, and their fertility was greatly reduced. Additionally, female mice lacking Nr2c2 exhibited behavioral abnormalities, including defects in maternal behavior.
Independently, Mu et al. (2004) found that Tr4 -/- mice were smaller than wildtype. Tr4 -/- mice exhibited varying degrees of behavioral defects, such as hypersensitivity to environmental stimuli. Male fertility was reduced in Tr4 -/- mice and was associated with delayed spermatogenesis and decreased sperm production.
Chen et al. (2005) reported that behavioral abnormalities in Tr4 -/- mice included mild trembling, unsteady gait, hyperreactivity upon manipulation, hind limb grasping, decreased tendency to explore surroundings, and impaired motor coordination and balance. Histologic examination of postnatal Tr4 -/- cerebellum revealed gross abnormalities in foliation, with loss of lobule VII in the anterior vermis. Laminations of Tr4 -/- cerebellar cortex were abnormal, and Purkinje cells showed aberrant dendritic arborization and loss of calbindin (see CALB1, 114050) staining. Developing Tr4 -/- cerebellum exhibited reduced expression of genes involved in cerebellar morphologic development.
Chang, C., da Silva, S. L., Ideta, R., Lee, Y., Yeh, S., Burbach, J. P. H. Human and rat TR4 orphan receptors specify a subclass of the steroid receptor superfamily. Proc. Nat. Acad. Sci. 91: 6040-6044, 1994. [PubMed: 8016112] [Full Text: https://doi.org/10.1073/pnas.91.13.6040]
Chang, C., Kokontis, J., Acakpo-Satchivi, L., Liao, S., Takeda, H., Chang, Y. Molecular cloning of new human TR2 receptors: a class of steroid receptor with multiple ligand-binding domains. Biochem. Biophys. Res. Commun. 165: 735-741, 1989. [PubMed: 2597158] [Full Text: https://doi.org/10.1016/s0006-291x(89)80028-2]
Chen, Y.-T., Collins, L. L., Uno, H., Chang, C. Deficits in motor coordination with aberrant cerebellar development in mice lacking testicular orphan nuclear receptor 4. Molec. Cell. Biol. 25: 2722-2732, 2005. [PubMed: 15767677] [Full Text: https://doi.org/10.1128/MCB.25.7.2722-2732.2005]
Collins, L. L., Lee, Y.-F., Heinlein, C. A., Liu, N.-C., Chen, Y.-T., Shyr, C.-R., Meshul, C. K., Uno, H., Platt, K. A., Chang, C. Growth retardation and abnormal maternal behavior in mice lacking testicular orphan nuclear receptor 4. Proc. Nat. Acad. Sci. 101: 15058-15063, 2004. [PubMed: 15477591] [Full Text: https://doi.org/10.1073/pnas.0405700101]
Hirose, T., Fujimoto, W., Yamaai, T., Kim, K. H., Matsuura, H., Jetten, A. M. TAK1: Molecular cloning and characterization of a new member of the nuclear receptor superfamily. Molec. Endocr. 8: 1667-1680, 1994. [PubMed: 7708055] [Full Text: https://doi.org/10.1210/mend.8.12.7708055]
Mu, X., Lee, Y.-F., Liu, N.-C., Chen, Y.-T., Kim, E., Shyr, C.-R., Chang, C. Targeted inactivation of testicular nuclear orphan receptor 4 delays and disrupts late meiotic prophase and subsequent meiotic divisions of spermatogenesis. Molec. Cell. Biol. 24: 5887-5899, 2004. [PubMed: 15199144] [Full Text: https://doi.org/10.1128/MCB.24.13.5887-5899.2004]
Nakajima, T., Fujino, S., Nakanishi, G., Kim, Y.-S., Jetten, A. M. TIP27: a novel repressor of the nuclear orphan receptor TAK1/TR4. Nucleic Acids Res. 32: 4194-4204, 2004. [PubMed: 15302918] [Full Text: https://doi.org/10.1093/nar/gkh741]
Yoshikawa, T., DuPont, B. R., Leach, R. J., Detera-Wadleigh, S. D. New variants of the human and rat nuclear hormone receptor, TR4: expression and chromosomal localization of the human gene. Genomics 35: 361-366, 1996. [PubMed: 8661150] [Full Text: https://doi.org/10.1006/geno.1996.0368]