Functional Interactions between Retinoic Acid Receptor-related Orphan Nuclear Receptor (RORα) and the Retinoic Acid Receptors in the Regulation of the γF-Crystallin Promoter

Tini, Mark; Fraser, R. A.; Giguère, Vincent

doi:10.1074/jbc.270.34.20156

Cited by 88 publications

(40 citation statements)

References 35 publications

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“…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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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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“…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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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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“…A number of these sites are also bound by one or more orphans or other conventional receptors as monomers (e.g. ROR (12)), homodimers (e.g. HNF-4 (13,14)), or as RXR heterodimers (e.g.…”

mentioning

confidence: 99%

Differential Transactivation by Two Isoforms of the Orphan Nuclear Hormone Receptor CAR

Choi¹,

Chung²,

Tzameli³

et al. 1997

Journal of Biological Chemistry

257

193

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We have identified a new murine orphan member of the nuclear hormone receptor superfamily, termed mCAR, that is closely related to the previously described human orphan MB67, referred to here as hCAR. Like hCAR, mCAR expression is highest in liver. In addition to the most abundant mCAR1 isoform, the mCAR gene expresses a truncated mCAR2 variant that is missing the C-terminal portion of the ligand binding/dimerization domain. The mCAR gene has 8 introns, and this mCAR2 variant is generated by a splicing event that skips the 8th exon. mCAR1, like hCAR, binds as a heterodimer with the retinoid X receptor to the retinoic acid response element from the promoter of the retinoic acid receptor ␤2 isoform. Consistent with its lack of a critical heterodimerization interface, the mCAR2 variant does not bind this site. Both mCAR1 and hCAR are apparently constitutive transcriptional activators. This activity is dependent on the presence of the conserved C-terminal AF-2 transcriptional activation motif. As expected from its inability to bind DNA, the mCAR2 variant neither transactivates by itself nor inhibits transactivation by hCAR or mCAR1.The nuclear hormone receptor superfamily includes the receptors for a number of potent biological regulators, such as steroids, retinoids, and thyroid hormone. With the recent addition of nuclear prostaglandin receptors (1, 2), and an oxysterol receptor (3), there are now more than 15 genes in mammalian genomes that encode such conventional receptors. An even larger set of genes encodes the orphan receptors, which are related to the conventional receptors but do not have known ligands. Particularly since individual genes for superfamily members frequently encode more than one isoform as a consequence of either alternative promoter utilization or alternative mRNA splicing, the total number of proteins that belong to the nuclear receptor superfamily is large.

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Functional Interactions between Retinoic Acid Receptor-related Orphan Nuclear Receptor (RORα) and the Retinoic Acid Receptors in the Regulation of the γF-Crystallin Promoter

Cited by 88 publications

References 35 publications

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

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

Activation of the mouse oxytocin promoter by the orphan receptor RORalpha

Differential Transactivation by Two Isoforms of the Orphan Nuclear Hormone Receptor CAR

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