Regulation of Peroxisome Proliferator-activated Receptor α-Induced Transactivation by the Nuclear Orphan Receptor TAK1/TR4

Yan, Zhong; Karam, Walid; Staudinger, Jeff; Medvedev, Alexander V.; Ghanayem, Burhan I.; Jetten, Anton M.

doi:10.1074/jbc.273.18.10948

Cited by 62 publications

(53 citation statements)

References 73 publications

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“…For example, COUP-TF1 can induce the 7␣-hydroxylase promoter activity via the DR4 binding site and repress myosin heavy chain promoter activity via a similar DR4 binding site (39). Similar differential modulation of target gene expression also occurred with TR4, via binding to similar DR1 binding sites (21,23).…”

Section: Discussionmentioning

confidence: 81%

“…The distribution of TR4 expression is ubiquitous in many tissues, including the central nervous system, adrenal gland, spleen, thyroid gland, and liver (16,19,23). Also, there are many other nuclear receptors expressed in the liver, such as HNF4␣ (24) and RXR␣/PPAR␣ (25,26).…”

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confidence: 99%

“…For example, TR4 induces reporters containing the DR1 site of human ciliary neurotrophic factor ␣ receptor promoter and the DR4 site of the ␣-myosin heavy chain promoter (19,20). In contrast, TR4 suppresses RXR␣/retinoic acid receptor (DR1), vitamin D3 receptor (DR3), and RXR␣/PPAR␣ (DR1)-mediated transactivation as shown by the reporter assay (21)(22)(23). These results suggest that TR4 may act as a negative regulator of its target genes containing hormone response elements (HREs) by competition with other nuclear receptors for binding to the HREs (21,23).…”

mentioning

confidence: 99%

“…In contrast, TR4 suppresses RXR␣/retinoic acid receptor (DR1), vitamin D3 receptor (DR3), and RXR␣/PPAR␣ (DR1)-mediated transactivation as shown by the reporter assay (21)(22)(23). These results suggest that TR4 may act as a negative regulator of its target genes containing hormone response elements (HREs) by competition with other nuclear receptors for binding to the HREs (21,23). In addition, our previous data showed that TR4 could also suppress androgen receptor-mediated transactivation via protein-protein interaction (22).…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 81%

mentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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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 plasmid pM-N-CoR was described previously (28). The expression plasmids pZeoSV-RTR encoding full-length mRTR, pSG5-VP16-RTR encoding the VP16(AD) fused to full-length mRTR, and pGEX-2TK-RTR encoding a GST-RTR fusion protein were described previously (23,28,31). The different pSG5-VP16-RTR deletion mutants were created by placing the VP16 activation domain at the amino terminus of various RTR fragments as described previously (28).…”

Section: Methodsmentioning

confidence: 99%

RAP80, a Novel Nuclear Protein That Interacts with the Retinoid-related Testis-associated Receptor

Yan

Kim

Jetten

2002

Journal of Biological Chemistry

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In this study, we describe the characterization of a novel nuclear protein, referred to as RAP80. The RAP80 cDNA was cloned from a human testis cDNA library and encodes a 719-amino acid protein containing two potential CX 2 CX 11 HX 3 C-type zinc finger motifs at its carboxylterminal region. Analysis of its genomic structure revealed that the RAP80 gene covers more than 90 kb and consists of 15 exons and 14 introns. Fluorescence in situ hybridization mapped the RAP80 gene to human chromosome 5q35. RAP80 mRNA is expressed in many human tissues, but its expression is particularly high in testis. In situ hybridization showed that RAP80 is highly expressed in germ cells of mouse testis but is not differentially regulated during spermatogenesis. Confocal microscopy showed that RAP80 is localized to the nucleus, where it is distributed in a speckled pattern. Deletion analysis showed that a bipartite nuclear localization signal at the amino terminus is important in mediating nuclear transport of RAP80. Monohybrid analysis showed that RAP80 might function as an active repressor of transcription. Mammalian two-hybrid analysis demonstrated that RAP80 was able to interact with the retinoid-related testis-associated receptor (RTR), an orphan receptor that has been implicated in the control of embryonic development and spermatogenesis. Pulldown analysis showed that RAP80 and RTR physically interact in vitro. Deletion and point mutation analyses revealed that part of the hinge domain of RTR is required for this interaction. RAP80 is able to inhibit the interaction of RTR with the co-repressor N-CoR likely by competing with N-CoR for RTR binding. Our results suggest that RAP80 may be functioning as a modulator of RTR signaling.The nuclear receptor superfamily is composed of a large number of ligand-dependent transcription factors that include nuclear orphan receptors for which a ligand has not yet been identified (1-4). Nuclear receptors share a common domain structure that includes an amino-terminal domain, a DNAbinding domain (DBD), 1 hinge domain, and a ligand-binding domain (LBD). These domains are involved in the recognition of specific DNA response elements, receptor dimerization, nuclear localization, and ligand binding and contain repressor and transactivation functions. Repression and activation of transcription by nuclear receptors are mediated through interactions with co-repressor and co-activators, respectively. Nuclear receptors have been demonstrated to regulate many physiological processes, including embryonic development and cell growth and differentiation and have been implicated in a number of human diseases (5-8). Less, however, is known about the role of many nuclear orphan receptors, including the retinoidrelated, testis-associated receptor (RTR), also referred to as germ cell nuclear factor (9, 10). The orphan receptor RTR (named NR6A1 by the Nuclear Receptor Nomenclature Committee) has been cloned from several species, including mouse (9, 10), human (11-14), zebrafish (15), and Xenopus laevis (16). Duri...

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PPARs and Cancer

Gill

Roberts²

2008

Protein Science Encyclopedia

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Originally published in: Cellular Proteins and Their Fatty Acids in Health and Disease. Edited by Asim K. Duttaroy and Friedrich Spener. Copyright © 2003 Wiley‐VCH Verlag GmbH & Co. KGaA Weinheim. Print ISBN: 3‐527‐30437‐0 The sections in this article are Introduction The PPAR Family PPARα Expression and Activation PPARα and Cancer Species Differences PPARα as a Therapeutic Target? PPARγ Expression and Activation PPARγ and Cancer PPARγ as a Therapeutic Target? PPARβ Expression and Activation PPARβ and Cancer PPARβ as a Therapeutic Target? Conclusions

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Regulation of Peroxisome Proliferator-activated Receptor α-Induced Transactivation by the Nuclear Orphan Receptor TAK1/TR4

Cited by 62 publications

References 73 publications

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

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

RAP80, a Novel Nuclear Protein That Interacts with the Retinoid-related Testis-associated Receptor

PPARs and Cancer

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