TR4 Orphan Receptor Represses the Human Steroid 21-Hydroxylase Gene Expression through the Monomeric AGGTCA Motif

Lee, Han-Jung; Lee, Yi-Fen; Chang, Chawnshang

doi:10.1006/bbrc.2001.5342

Cited by 16 publications

(13 citation statements)

References 40 publications

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“…For several years, scientists worked to determine which DNA sequence(s) would be a binding target for TR4. In addition to binding to direct repeat elements, TR4 was shown to bind to the monomeric AGGTCA motif and subsequently suppress the expression of steroid 21-hydroxylase and oxytocin (39,40). Therefore, it is possible that these receptors also target the same DNA sequences (for example, direct repeat 1, AGGTCAAAGGTCA), or hormone response elements, in gene promoters.…”

Section: Putative Regulatory Effects Of Tr4mentioning

confidence: 99%

The roles of testicular orphan nuclear receptor 4 (TR4) in cerebellar development

et al. 2008

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Since Testicular Receptor 4 (TR4) was cloned, efforts have been made to elucidate its physiological function. To examine the putative functions of TR4, the conventional TR4 knockout (TR4(-/-)) mouse model was generated. Throughout postnatal and adult stages, TR4(-/-) mice exhibited behavioral deficits in motor coordination, suggesting impaired cerebellar function. Histological examination of the postnatal and adult TR4(-/-) cerebellum revealed gross abnormalities in foliation. Further analyses demonstrated changes in the lamination of the TR4(-/-) cerebellar cortex, including reduction in the thickness of both the molecular layer (ML) and the internal granule layer (IGL). Analyses of the developing TR4(-/-) cerebellum indicate that the lamination irregularities observed may result from disrupted granule cell proliferation within the external granule cell layer (EGL), delayed inward migration of post-mitotic granule cells, and increased apoptosis during cerebellar development. In addition, abnormal development of Purkinje cells was observed in the postnatal TR4(-/-) cerebellum, as indicated by aberrant dendritic arborization. In postnatal, neuronal-specific TR4 knockout mice, architectural changes in the cerebellum were similar to those seen in TR4(-/-) animals, suggesting that TR4 function in neuronal lineages might be important for cerebellar morphogenesis, and that the effect on Purkinje cell development is likely mediated by changes elsewhere, such as in granule cells, or is highly dependent on developmental stage. Together, our findings from various TR4 knockout mouse models suggest that TR4 is required for normal cerebellar development and that failure to establish proper cytoarchitecture results in dysfunction of the cerebellum and leads to abnormal behavior.

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Section: Putative Regulatory Effects Of Tr4mentioning

confidence: 99%

The roles of testicular orphan nuclear receptor 4 (TR4) in cerebellar development

et al. 2008

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“…The TR4 gene encodes a protein of 596 amino acids with a molecular mass of 67 kDa (14,15) and binds to a consensus HRE composed of an AGGTCA direct repeat (DR) with spacing from zero to six nucleotides (16,17). Molecular structure analyses indicate that TR4 belongs to the nuclear receptor superfamily, but its biological function remains largely unknown.…”

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confidence: 99%

Loss of TR4 Orphan Nuclear Receptor Reduces Phosphoenolpyruvate Carboxykinase–Mediated Gluconeogenesis

et al. 2007

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OBJECTIVE-Regulation of phosphoenolpyruvate carboxykinase (PEPCK), the key gene in gluconeogenesis, is critical for glucose homeostasis in response to quick nutritional depletion and/or hormonal alteration. RESEARCH DESIGN/METHODS AND RESULTS-Here, we identified the testicular orphan nuclear receptor 4 (TR4) as a key PEPCK regulator modulating PEPCK gene via a transcriptional mechanism. TR4 transactivates the 490-bp PEPCK promotercontaining luciferase reporter gene activity by direct binding to the TR4 responsive element (TR4RE) located at Ϫ451 to Ϫ439 in the promoter region. Binding to TR4RE was confirmed by electrophoretic mobility shift and chromatin immunoprecipitation assays. Eliminating TR4 via knockout and RNA interference (RNAi) in hepatocytes significantly reduced the PEPCK gene expression and glucose production in response to glucose depletion. In contrast, ectopic expression of TR4 increased PEPCK gene expression and hepatic glucose production in human and mouse hepatoma cells. Mice lacking TR4 also display reduction of PEPCK expression with impaired gluconeogenesis.CONCLUSIONS-Together, both in vitro and in vivo data demonstrate the identification of a new pathway, TR4 3 PEPCK 3 gluconeogenesis 3 blood glucose, which may allow us to modulate metabolic programs via the control of a new key player, TR4, a member of the nuclear receptor superfamily.

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“…TR4 usually regulates target gene expression via binding to DRs as a TR4 homodimer or heterodimer with TR2 (Lee et al 1998). Interestingly, a previous report showed that TR4 is also able to bind to monomeric AAAGGTCA-like sequences (Lee et al 2001), strongly suggesting that these two NRs might functionally cross-talk with each other to fine-tune adipocyte biology. As expected, Nur77 inhibited TR4 transcriptional activity at least in part by suppressing TR4 binding to TR4REs.…”

Section: Discussionmentioning

confidence: 99%

“…TR4 functions dominantly as a homodimer via direct binding to DRs. In addition, TR4 is also able to bind to a single AGGTCA-like sequence as a monomer (Lee et al 2001). Like many other NRs, TR4 is known to participate in other NR signaling pathways through binding competition for coactivators or DNA-binding sites located in the promoter of target genes or through heterodimer formation via protein-protein interactions (Lee et al 1998;Shyr et al 2002).…”

Section: Introductionmentioning

confidence: 99%

Nur77 inhibits TR4-induced PEPCK expression in 3T3-L1 adipocytes

Kim

2012

Animal Cells and Systems

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Nur77 is a member of the nuclear receptor 4A (NR4A) subgroup, which has been implicated in energy metabolism. Although Nur77 is found in adipose tissue, where TR4 plays a key role in lipid homeostasis, the role of Nur77 in adipogenesis is still controversial. Although the Nur77 responsive element (AAAGGTCA) is partially overlapped with TR4-binding sites (AGGTCA n AGGTCA: n 00Á6), the regulatory role of Nur77 in TR4 function associated with adipocyte biology remains unclear. Here, we found that Nur77 inhibits adipogenesis and TR4 transcriptional activity. Treatment with a Nur77 agonist, 1,1-bis(3?-indolyl)-1-(p-anisyl)-methane, during 3T3-L1 adipocyte differentiation reduced adipogenesis. In reporter gene analysis, Nur77 specifically suppressed TR4 transcription activity but had little effect on PPARg transcription activity. Consistently, Nur77 also suppressed TR4-induced promoter activity of the TR4 target gene PEPCK, which is known to be important for glyceroneogenesis in adipose tissue. Furthermore, Nur77 suppressed TR4 binding to TR4 response elements without direct interaction with TR4, suggesting that Nur77 may inhibit TR4 transcription activity via binding competition for TR4-binding sites. Furthermore, DIM-C-pPhOCH 3 substantially suppressed TR4-induced PEPCK expression in 3T3-L1 adipocytes.Together, our data demonstrate that Nur77 plays an inhibitory role in TR4-induced PEPCK expression in 3T3-L1 adipocytes.

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TR4 Orphan Receptor Represses the Human Steroid 21-Hydroxylase Gene Expression through the Monomeric AGGTCA Motif

Cited by 16 publications

References 40 publications

The roles of testicular orphan nuclear receptor 4 (TR4) in cerebellar development

The roles of testicular orphan nuclear receptor 4 (TR4) in cerebellar development

Loss of TR4 Orphan Nuclear Receptor Reduces Phosphoenolpyruvate Carboxykinase–Mediated Gluconeogenesis

Nur77 inhibits TR4-induced PEPCK expression in 3T3-L1 adipocytes

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