Identification of Natural Monomeric Response Elements of the Nuclear Receptor RZR/ROR. THEY ALSO BIND COUP-TF HOMODIMERS

Schräder, Magdalena; Danielsson, Christian; Wiesenberg, Irmgard; Carlberg, Carsten

doi:10.1074/jbc.271.33.19732

Cited by 99 publications

(92 citation statements)

References 48 publications

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“…This is compatible with the accepted concept that COUP-TF binds as a dimer, whereas ROR binds as a monomer. Indeed, COUP-TF homodimers have been shown to bind with high affinity to monomeric ROR/RZR response elements (Schräder et al 1996). In addition, COUP-TFII is also able to bind to a more downstream area ( 75 to 100) containing three (inverted) GGTCA repeats (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Activation of the mouse oxytocin promoter by the orphan receptor RORalpha

Chu

Zingg

1999

Journal of Molecular Endocrinology

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Although an increasing number of nuclear orphan receptors have recently been identified, the number of known naturally occurring genes that are directly regulated by orphan receptors is still small. We have shown previously that the gene encoding the neuropeptide oxytocin (OT) is negatively regulated by the orphan receptors chicken ovalbumin upstream transcription factor I (COUP-TFI) and II. Here we show that the mouse OT gene promoter is activated by ROR , a representative of the ROR/RZR orphan receptor subfamily. Using promoter/chloramphenicol acetyltransferase reporter constructs in heterologous transfection assays, we determined that ROR action induces a <6-fold increase in promoter activity. By 5 and 3 deletion analysis, DNase footprint analysis and electrophoretic mobility shift assays, we found that ROR action is mediated by two 14 bp regions centered at 160 and 180 nucleotides upstream of the transcriptional initiation site. Both sites contain significant sequence identities with an established ROR recognition sequence. Mutations in either or both of these sites reduce significantly RORinduced activation of the OT promoter. In view of the strong transcriptional activation exerted by ROR on the OT gene promoter and the widespread distribution of different members of the ROR/RZR family, interactions between ROR/RZR isoforms and the OT gene may form part of the multifactorial regulatory mechanisms that control OT gene expression in different tissues.

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Section: Resultsmentioning

confidence: 99%

“…WAF/CIP1 and Purkinje cell protein-2 (Steinhilber et al 1995, Tini et al 1995, Schräder et al 1996, Vu-Dac et al 1997). …”

Section: Introductionmentioning

confidence: 99%

Activation of the mouse oxytocin promoter by the orphan receptor RORalpha

Chu

Zingg

1999

Journal of Molecular Endocrinology

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“…It remains to be determined whether ROR␣1 interacts with the TATA box-binding protein or rather competes for its binding, but its close localization to the TATA box and the requirement of an AT-rich nucleotide stretch for binding suggests that ROR␣ may compete for TATA box-binding protein binding resulting in a transcription initiation complex of higher activity. Although surprising, the identification of a potential similar TATA box overlapping RORE in the rat bone sialoprotein gene (36) suggests that ROR␣ may have a more general function as a component of the basal transcription machinery.…”

Section: Apoa-i Gene Regulation By Ror␣mentioning

confidence: 99%

“…However, the presence of the reported sequence requirements for ROR␣2 binding (a T at position Ϫ1 and an A at Ϫ4 relative to the AGGTCA half-site) in the apoA-I RORE (16,18) contrasts to the absence of ROR␣2 binding and transactivation on this RORE and suggests that other DNA sequence differences may also contribute to differentiate ROR␣1 from ROR␣2 binding. Computer homology searches allowed the identification of ROREs in a variety of genes, such as the human and mouse N-myc proto-oncogene, the mouse cellular retinol-binding protein I, chicken ␥F-crystallin, rat bone sialoprotein, mouse Purkinje cell protein 2, and human p21 WAF1/CIP1 (16,(35)(36)(37). In addition, a RORE has also been identified in the promoter of the 5-lipoxygenase gene, which may mediate the negative regulation of its expression by melatonin, a possible ligand for ROR/RZR␣ and ROR/RZR␤ (38 -40).…”

Section: Apoa-i Gene Regulation By Ror␣mentioning

confidence: 99%

Transcriptional Regulation of Apolipoprotein A-I Gene Expression by the Nuclear Receptor RORα

Vu‐Dac¹,

Gervois²,

Grötzinger³

et al. 1997

Journal of Biological Chemistry

127

116

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Since elevated concentrations of plasma high density lipoprotein (HDL) and its major apolipoprotein (apo), apoA-I, confer protection against atherosclerosis, considerable research efforts have focussed on the identification of factors regulating apoA-I gene expression in an attempt to increase its production. Nuclear receptors are interesting candidates because they are transcription factors whose activity is ligand-dependent. In the present study we identified the orphan receptor ROR␣1 as an activator of apoA-I gene transcription. In apoA-Iexpressing intestinal Caco-2 cells, overexpression of the ROR␣1, but not the ROR␣2 or ROR␣3 isoforms, increased rat apoA-I gene transcription. Deletion and sitedirected mutagenesis experiments identified a functional ROR-responsive element (RORE) in the rat and mouse apoA-I gene promoters, which overlaps with the TATA box. Gel shift experiments indicated that this RORE binds the ROR␣1 isoform, but not the ROR␣2 or ROR␣3 isoforms. Furthermore, compared with wild type mice, apoA-I mRNA levels were significantly lower in small intestines of staggerer mice homozygous for a deletion in the ROR␣ gene. In addition, reverse transcriptase-polymerase chain reaction analysis revealed the expression of ROR␣ in small intestinal epithelium and in Caco-2 cells. These data indicate a novel, physiological role for ROR␣1 in the regulation of genes involved in lipid and lipoprotein metabolism and possibly in the development of metabolic diseases, such as atherosclerosis.Results from several epidemiological studies have demonstrated that plasma concentrations of high density lipoprotein (HDL) 1 and its major protein component, apolipoprotein (apo) A-I, are inversely correlated to the development of coronary artery disease (1-4). In addition, studies in transgenic mice and rabbits have shown that overexpression of the human apoA-I gene results in increased plasma HDL and apoA-I concentrations and confers protection against atherogenesis (5, 6), whereas elimination of the apoA-I gene by homologous recombination leads to a profound hypo-␣-lipoproteinemia (7). Therefore, a thorough knowledge of the factors controlling apoA-I production and metabolism is essential to understand the causes of hypo-␣-lipoproteinemia, the most common lipoprotein abnormality in patients with coronary artery disease (8).To identify factors regulating apoA-I gene expression, we focussed our attention on various members of the superfamily of nuclear receptors. Nuclear receptors are transcription factors, which upon activation by specific ligands bind to response elements located in the regulatory regions of target genes and thereby modulate their transcriptional activity (9). As such nuclear receptors translate signals coming from the environment into changes in gene expression and are therefore interesting targets for pharmacological intervention. The largest class of nuclear receptors is constituted by the orphan receptors, for which no ligands have yet been identified (10). Furthermore, the physiological functions of mos...

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“…RORA has also been suggested to be involved in lipid metabolism, to possess immunomodulatory activity and to mediate the antiarthritic properties of a class of thiazolidinediones (Missbach et al, 1996). ROREs (ROR response elements), to which RORA protein binds, have been identified in the promoter region of cell cycle-related genes, such as those of the cyclin-dependent kinase (CDK) inhibitor p21 WAF1/CIP1 (Schrader et al, 1996), and of cyclin A, as well as in the promoter of N-myc (Lee et al, 1984;Nau et al, 1986), a gene whose amplification appears to be related to the development of several tumors. It has been reported that ligand-induced activation of RORA significantly reduces the growth of the murine colon 38 adenocarcinoma (Pawlikowski et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

RORA, a large common fragile site gene, is involved in cellular stress response

et al. 2006

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Common fragile sites (CFSs) are large genomic regions present in all individuals that are highly unstable and prone to breakage and rearrangement, especially in cancer cells with genomic instability. Eight of the 90 known CFSs have been precisely defined and five of these span genes that extend from 700 kb to over 1.5 Mb of genomic sequence. Although these genes reside within some of the most unstable chromosomal regions in the human genome, they are highly conserved evolutionarily. These genes are targets for large chromosomal deletions and rearrangements in cancer and are frequently inactivated in multiple tumor types. There is also an association between these genes and cellular responses to stress. Based upon the association between large genes and CFSs, we began to systematically test other large genes derived from chromosomal regions that were known to contain a CFS. In this study, we demonstrate that the 730 kb retinoic acid receptor-related orphan receptor alpha (RORA) gene is derived from the middle of the FRA15A (15q22.2) CFS. Although this gene is expressed in normal breast, prostate and ovarian epithelium, it is frequently inactivated in cancers that arise from these organs. RORA was previously shown to be involved in the cellular response to hypoxia and here we demonstrate changes in the amount of RORA message produced in cells exposed to a variety of different cellular stresses. Our results demonstrate that RORA is another very large CFS gene that is inactivated in multiple tumors. In addition, RORA appears to play a critical role in responses to cellular stress, lending further support to the idea that the large CFS genes function as part of a highly conserved stress response network that is uniquely susceptible to genomic instability in cancer cells.

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Identification of Natural Monomeric Response Elements of the Nuclear Receptor RZR/ROR. THEY ALSO BIND COUP-TF HOMODIMERS

Cited by 99 publications

References 48 publications

Activation of the mouse oxytocin promoter by the orphan receptor RORalpha

Activation of the mouse oxytocin promoter by the orphan receptor RORalpha

Transcriptional Regulation of Apolipoprotein A-I Gene Expression by the Nuclear Receptor RORα

RORA, a large common fragile site gene, is involved in cellular stress response

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