Differential Regulation of the N-<i>myc</i> Proto-Oncogene by RORα and RVR, Two Orphan Members of the Superfamily of Nuclear Hormone Receptors

Dussault, Isabelle; Giguère, Vincent

doi:10.1128/mcb.17.4.1860

Cited by 63 publications

(30 citation statements)

References 45 publications

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“…It was previously demonstrated that RORA binds as a monomer or homodimer to regulatory ROREs in the promoter region of its target genes, which include one core motif AGGTCA or two direct AGGTCA repeats spaced by two nucleotides preceded by a six nucleotide long AT-rich sequence (Giguere et al, 1994). Several genes have been identified as potential target genes of RORA including the CDK inhibitor p21 and N-myc (Dussault and Giguere, 1997), which are closely related to human cancer development. In this study, a significantly inhibited cell growth was observed when the RORA gene was re-introduced into MCF12F cells.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

confidence: 99%

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

et al. 2006

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“…The expression of RORalpha, a transcription factor that belongs to the family of orphan nuclear receptor tyrosine kinases, was increased in MCL. Response elements for this factor are present in cell cycle regulating genes such as N-myc, 19 suggesting that it is involved in the control of cell proliferation. Furthermore, RORalpha has been shown to negatively regulate inflammatory responses.…”

Section: Differentially Expressed Genes Between MCL and Reactive Lympmentioning

confidence: 99%

High level of cannabinoid receptor 1, absence of regulator of G protein signalling 13 and differential expression of Cyclin D1 in mantle cell lymphoma

et al. 2003

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Mantle cell lymphoma (MCL) is a moderately aggressive B-cell lymphoma that responds poorly to currently used therapeutic protocols. In order to identify tumour characteristics that improve the understanding of biology of MCL, analysis of oligonucleotide microarrays were used to define specific gene expression profiles. Biopsy samples of MCL cases were compared to reactive lymphoid tissue. Among genes differentially expressed in MCL were genes that are involved in the regulation of proliferation, cell signalling, adhesion and homing. Furthermore, some genes with previously unknown function, such as C11orf32, C2orf10, TBC1D9 and ABCA6 were found to be differentially expressed in MCL compared to reactive lymphoid tissue. Of special interest was the high expression of the cannabinoid receptor 1 (CB1) gene in all MCL cases analysed. These results were further confirmed at the cellular and protein level by immunocytochemical staining and immunoblotting of MCL cells. Furthermore, there was a reduced expression of a regulator of G protein signalling, RGS13 in all MCLs, with a complete absence in the majority of cases while present in control lymphoid tissue. These results were further confirmed by PCR. Sequencing of the RGS13 gene revealed changes suggesting polymorphisms, indicating that downregulation of the expression of RGS13 is not related to mutations, but may serve as a new specific marker for MCL. Moreover, comparison between individual cases of MCL, revealed that the CCND1 gene appears to be differently expressed in MCL cases with high vs low proliferative activity.

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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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Differential Regulation of the N-myc Proto-Oncogene by RORα and RVR, Two Orphan Members of the Superfamily of Nuclear Hormone Receptors

Cited by 63 publications

References 45 publications

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

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

High level of cannabinoid receptor 1, absence of regulator of G protein signalling 13 and differential expression of Cyclin D1 in mantle cell lymphoma

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

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