Human and rat TR4 orphan receptors specify a subclass of the steroid receptor superfamily.

Chang, Chawnshang; Silva, S L Da; Ideta, Ritsuro; Lee, Y; Yeh, Shuyuan; Burbach, J. P. H.

doi:10.1073/pnas.91.13.6040

Cited by 139 publications

(143 citation statements)

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(20 reference statements)

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“…The testicular receptor 4 (TR4) was first cloned from prostate and testis cDNA libraries and is highly homologous to the TR2 nuclear receptor [1]. The molecular structure analyses indicated that TR4 belongs to the nuclear receptor superfamily that may control the expression of target genes involved in developmental, physiological, and behavioral responses from the cellular level to that of the whole organism.…”

Section: Introductionmentioning

confidence: 99%

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Deficiency in TR4 nuclear receptor abrogates Gadd45a expression and increases cytotoxicity induced by ionizing radiation

Yan

Lee

Ting

et al. 2012

Cellular and Molecular Biology Letters

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The testicular receptor 4 (TR4) is a member of the nuclear receptor superfamily that controls various biological activities. A protective role of TR4 against oxidative stress has recently been discovered. We here examined the protective role of TR4 against ionizing radiation (IR) and found that small hairpin RNA mediated TR4 knockdown cells were highly sensitive to IR-induced cell death. IR exposure increased the expression of TR4 in scramble control small hairpin RNA expressing cells but not in TR4 knockdown cells. Examination of IR-responsive molecules found that the expression of Gadd45a, the growth arrest and DNA damage response gene, was dramatically decreased in Tr4 deficient (TR4KO) mice tissues and could not respond to IR stimulation in TR4KO mouse embryonic fibroblast cells. This TR4 regulation of GADD45A was at the transcriptional level. Promoter analysis identified four potential TR4 response elements located in intron 3 and exon 4 of the GADD45A gene. Reporter and chromatin immunoprecipitation (ChIP) assays provided evidence indicating that TR4 regulated the GADD45A expression through TR4 response elements located in intron 3 of the GADD45A gene. Together, we find that TR4 is essential in protecting cells from IR stress. Upon IR challenges, TR4 expression is increased, thereafter inducing GADD45A through transcriptional regulation. As GADD45A is directly involved in the DNA repair pathway, this suggests that TR4 senses genotoxic stress and up-regulates GADD45A expression to protect cells from IR-induced genotoxicity.

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Section: Introductionmentioning

confidence: 99%

“…The structural features common to nuclear receptors include those required for ligand binding, dimerization, DNA binding, and transactivation. TR4 has been an orphan nuclear receptor without an identified ligand since it was cloned in 1994 [1]. Recently, Xie et al .…”

Section: Introductionmentioning

confidence: 99%

Deficiency in TR4 nuclear receptor abrogates Gadd45a expression and increases cytotoxicity induced by ionizing radiation

Yan

Lee

Ting

et al. 2012

Cellular and Molecular Biology Letters

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“…These findings suggest that these nuclear receptors may play important roles in viral transcription. The detailed mechanisms of how the core promoter is differentially regulated by these nuclear receptors remain unclear.The testicular orphan receptor 4 (TR4) (NR2C2) is an orphan member of the nuclear receptor superfamily (15)(16)(17). This family includes classic steroid hormone receptors, the thyroid hormone receptor, the retinoid receptors, and many nuclear orphan receptors whose physiological ligands have not been identified (18).…”

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confidence: 99%

“…The testicular orphan receptor 4 (TR4) (NR2C2) is an orphan member of the nuclear receptor superfamily (15)(16)(17). This family includes classic steroid hormone receptors, the thyroid hormone receptor, the retinoid receptors, and many nuclear orphan receptors whose physiological ligands have not been identified (18).…”

mentioning

confidence: 99%

“…Most nuclear receptors bind to their cognate ligands, translocate into the nucleus, and bind to the specific HREs to turn on their downstream target genes. TR4 was isolated from human prostate and testis cDNA libraries and is considered to be an orphan receptor, because its ligand has not been found (15). Our previous data showed that TR4 recognizes different AGGTCA direct repeat (DR) sequences either inducing or suppressing its target genes.…”

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Suppression of Hepatitis B Virus Core Promoter by the Nuclear Orphan Receptor TR4

Lin

Lee

et al. 2003

Journal of Biological Chemistry

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The TR4 orphan receptor is a member of the nuclear receptor superfamily that modulates gene expression via binding to the AGGTCA direct repeat hormone response element. Here we report a functional study of TR4 interaction with the core promoter of the hepatitis B virus (HBV). 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. TR4 also can enhance the activity of a synthetic luciferase reporter linked with four copies of TR4RE-HBV in either liver HepG2 or non-liver H1299 cells in a dose-dependent manner. Surprisingly, TR4 represses the activity of a luciferase reporter containing the entire HBV genome sequences. Moreover, mutation of this TR4RE-HBV site in the HBV core promoter diminishes the TR4 suppression effect. This TR4-induced suppression of HBV core promoter activity is further confirmed by primer extension analysis of the HBV core RNAs, showing that TR4 represses both pre-core and core mRNAs. Further dissection of this repressive mechanism indicates that TR4 may suppress the HBV core promoter activity via repressing HNF4␣-mediated transactivation by protein-protein interactions without inhibition of HNF4␣ DNA binding. Furthermore, our results indicate that the N-and C-terminal regions of TR4 protein are required for TR4-HNF4␣ interaction. It is possible that TR4-HNF4␣ interaction may block the HNF4␣ function that results in the suppression of HBV gene expression. Together, these results demonstrate that TR4 can serve as a negative modulator in the transcriptional regulation of HBV core gene expression.Hepatitis B virus (HBV) 1 is a small virus with a 3.2-kb partially double-stranded DNA genome, containing four open reading frames: the surface antigen, the core antigen, the polymerase, and the X protein (1, 2). HBV is a major pathogen causing acute and chronic liver diseases, such as cirrhosis and hepatocellular carcinoma (3, 4). HBV transcripts are regulated by the transcriptional control of four different promoters and two enhancer elements (5). HBV is replicated from a RNA intermediate as a template for reverse transcription (1). The core promoter controls the expression of the 3.5-kb core mRNA (C mRNA) as the template for replication, and the expression of the pre-core mRNA (pre-C mRNA) for the translation of the HBeAg precursor (6). Recently, multiple binding sites for liverspecific or ubiquitous transcription factors and several hormone response elements (HRE) have been identified in the core promoter region, including Sp1 (7, 8), TATA-binding protein (9), HNF3 (10), HNF4␣ (11), C/EBP (12), and other members of the nuclear receptor superfamily, such as the retinoid X receptor (RXR␣), peroxisome proliferator-activated receptor (PPAR␣), COUP-TF1, and ARP1 (13). For example, HNF4␣ and RXR␣/PPAR␣ can stimulate the expression of the 3.5-kb core RNA, COUP-TF1 suppresses the expression of both the pre-C RNA and C RNA, and TR2 preferentially represses the expression of ...

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Molecular cloning and characterization of a mouse nuclear orphan receptor expressed in embryos and testes

Lee

Chang

1996

Mol. Reprod. Dev.

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Human and rat TR4 orphan receptors specify a subclass of the steroid receptor superfamily.

Cited by 139 publications

References 20 publications

Deficiency in TR4 nuclear receptor abrogates Gadd45a expression and increases cytotoxicity induced by ionizing radiation

Deficiency in TR4 nuclear receptor abrogates Gadd45a expression and increases cytotoxicity induced by ionizing radiation

Suppression of Hepatitis B Virus Core Promoter by the Nuclear Orphan Receptor TR4

Molecular cloning and characterization of a mouse nuclear orphan receptor expressed in embryos and testes

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