scholarly journals Hypoxia-induced Activation of the Retinoic Acid Receptor-related Orphan Receptor α4 Gene by an Interaction between Hypoxia-inducible Factor-1 and Sp1

2004 ◽  
Vol 279 (15) ◽  
pp. 15025-15031 ◽  
Author(s):  
Naoki Miki ◽  
Megumi Ikuta ◽  
Takashi Matsui
Keyword(s):  
Retinoic Acid ◽  
Retinoic Acid Receptor ◽  
Hypoxia Inducible Factor ◽  
Orphan Receptor ◽  
Acid Receptor ◽  
Hypoxia Inducible Factor 1

scholarly journals The gene encoding human retinoic acid-receptor-related orphan receptor α is a target for hypoxia-inducible factor 1

2004 ◽  
Vol 384 (1) ◽  
pp. 79-85 ◽  
Author(s):  
Caroline CHAUVET ◽  
Brigitte BOIS-JOYEUX ◽  
Edurne BERRA ◽  
Jacques POUYSSEGUR ◽  
Jean-Louis DANAN
Keyword(s):  
Retinoic Acid ◽  
Cell Lines ◽  
Retinoic Acid Receptor ◽  
Hypoxia Inducible Factor ◽  
Dominant Negative ◽  
Orphan Receptor ◽  
Luciferase Reporter ◽  
Translation Initiation Site ◽  
Acid Receptor ◽  
Hypoxia Inducible Factor 1

Retinoic acid-receptor-related orphan receptor (ROR) α is a nuclear receptor involved in many pathophysiological processes such as cerebellar ataxia, inflammation, atherosclerosis and angiogenesis. In the present study we first demonstrate that hypoxia increases the amount of Rora transcripts in a wide panel of cell lines derived from diverse tissues. In addition, we identified a functional promoter sequence upstream of the first exon of the human Rora gene, spanning −487 and −45 from the translation initiation site of RORα1. When cloned in a luciferase reporter vector, this sequence allowed the efficient transcription of the luciferase gene in several cell lines. Interestingly, the activity of the Rora promoter was enhanced by hypoxia in HepG2 human hepatoma cells, and this effect was dependent on an HRE (hypoxia response element) spanning from −229 to −225. Using electrophoretic-mobility-shift assays, we showed that HIF-1 (hypoxia-inducible factor 1), which plays a key role in the transcriptional response to hypoxia, bound to this HRE. Overexpression of HIF-1α increased the activity of the Rora promoter through the HRE. Overexpression of a dominant-negative form of HIF-1α producing transcriptionally inactive HIF-1α/HIF-1β dimers abolished hypoxic activation of the Rora promoter. This indicated that HIF-1 is involved in the response of RORα to hypoxia. Taken together, our data reveal Rora as a new HIF-1 target gene. This illustrates, at the molecular level, the existence of cross-talk between signalling pathways mediated by HIF-1 and those mediated by nuclear receptors.

scholarly journals Hepatocyte nuclear factor-6 stimulates transcription of the alpha-fetoprotein gene and synergizes with the retinoic-acid-receptor-related orphan receptor alpha-4

2003 ◽  
Vol 369 (3) ◽  
pp. 583-591 ◽  
Author(s):  
Habib NACER-CHERIF ◽  
Brigitte BOIS-JOYEUX ◽  
Guy G. ROUSSEAU ◽  
Frédéric P. LEMAIGRE ◽  
Jean-Louis DANAN
Keyword(s):  
Retinoic Acid ◽  
Retinoic Acid Receptor ◽  
Orphan Receptor ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Acid Receptor ◽  
Splicing Isoforms ◽  
Liver Gene ◽  
A Site ◽  
Putative Binding Site

The rat α-fetoprotein (afp) gene is controlled by three enhancers whose function depends on their interaction with liver-enriched transcription factors. The afp enhancer III, located at −6kb, is composed of three regions that act in synergy. Two of these regions, called s1 and s2, contain a putative binding site for hepatocyte nuclear factor-6 (HNF-6). This factor is the prototype of the ONECUT family of cut-homoeodomain proteins and is a known regulator of liver gene expression in adults and during development. We show here that the two splicing isoforms of HNF-6 bind to a site in the s1 region and in the s2 region. The core sequence of the s1 site corresponds to none of the known HNF-6 binding sites. Nevertheless, the binding properties of the s1 site are identical with those of the s2 site and of previously characterized HNF-6 binding sequences. The HNF-6 consensus should therefore be rewritten as DRRTCVATND. Binding of HNF-6 to the s1 and s2 sites requires both the cut and the homoeo domains, is co-operative and induces DNA bending. HNF-6 strongly stimulates the activity of the afp enhancer III in transient transfection experiments. This effect requires the stereo-specific alignment of the two HNF-6 sites. Moreover, HNF-6 stimulates the enhancer in synergy with the retinoic-acid-receptor-related orphan receptor α (RORα), which binds to a neighbouring site in the s1 region. Thus expression of the afp gene requires functional interactions between HNF-6 molecules and between HNF-6 and RORα.

scholarly journals Orphan Receptor COUP-TF Is Required for Induction of Retinoic Acid Receptor β, Growth Inhibition, and Apoptosis by Retinoic Acid in Cancer Cells

2000 ◽  
Vol 20 (3) ◽  
pp. 957-970 ◽  
Author(s):  
Bingzhen Lin ◽  
Guo-quan Chen ◽  
Dongmei Xiao ◽  
Siva Kumar Kolluri ◽  
Xihua Cao ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Growth Inhibition ◽  
Cancer Cells ◽  
Retinoic Acid Receptor ◽  
Critical Role ◽  
Orphan Receptor ◽  
Dependent Manner ◽  
Anticancer Activities ◽  
Transient Transfection Assay ◽  
Acid Receptor

ABSTRACT Retinoic acid receptor β (RARβ) plays a critical role in mediating the anticancer effects of retinoids. Expression of RARβ is highly induced by retinoic acid (RA) through a RA response element (βRARE) that is activated by heterodimers of RARs and retinoid X receptors (RXRs). However, RARβ induction is often lost in cancer cells despite expression of RARs and RXRs. In this study, we provide evidence that orphan receptor COUP-TF is required for induction of RARβ expression, growth inhibition, and apoptosis by RA in cancer cells. Expression of COUP-TF correlates with RARβ induction in a variety of cancer cell lines. In addition, stable expression of COUP-TF in COUP-TF-negative cancer cells restores induction of RARβ expression, growth inhibition, and apoptosis by RA, whereas inhibition of COUP-TF by expression of COUP-TF antisense RNA represses the RA effects. In a transient transfection assay, COUP-TF strongly induced transcriptional activity of the RARβ promoter in a RA- and RARα-dependent manner. By mutation analysis, we demonstrate that the effect of COUP-TF requires its binding to a DR-8 element present in the RARβ promoter. The binding of COUP-TF to the DR-8 element synergistically increases the RA-dependent RARα transactivation function by enhancing the interaction of RARα with its coactivator CREB binding protein. These results demonstrate that COUP-TF, by serving as an accessory protein for RARα to induce RARβ expression, plays a critical role in regulating the anticancer activities of retinoids.

scholarly journals Unraveling the physiological roles of retinoic acid receptor-related orphan receptor α

2021 ◽  
Author(s):  
Ji Min Lee ◽  
Hyunkyung Kim ◽  
Sung Hee Baek
Keyword(s):  
Retinoic Acid ◽  
Molecular Mechanisms ◽  
Cancer Metabolism ◽  
Metabolic Diseases ◽  
Retinoic Acid Receptor ◽  
Critical Role ◽  
Orphan Receptor ◽  
Orphan Nuclear Receptor ◽  
Functional Link ◽  
Acid Receptor

AbstractRetinoic acid receptor-related orphan receptor-α (RORα) is a member of the orphan nuclear receptor family and functions as a transcriptional activator in response to circadian changes. Circadian rhythms are complex cellular mechanisms regulating diverse metabolic, inflammatory, and tumorigenic gene expression pathways that govern cyclic cellular physiology. Disruption of circadian regulators, including RORα, plays a critical role in tumorigenesis and facilitates the development of inflammatory hallmarks. Although RORα contributes to overall fitness among anticancer, anti-inflammatory, lipid homeostasis, and circadian clock mechanisms, the molecular mechanisms underlying the mode of transcriptional regulation by RORα remain unclear. Nonetheless, RORα has important implications for pharmacological prevention of cancer, inflammation, and metabolic diseases, and understanding context-dependent RORα regulation will provide an innovative approach for unraveling the functional link between cancer metabolism and rhythm changes.

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