scholarly journals Retinoic acid receptor-related orphan receptor (ROR) α4 is the predominant isoform of the nuclear receptor RORα in the liver and is up-regulated by hypoxia in HepG2 human hepatoma cells

2002 ◽  
Vol 364 (2) ◽  
pp. 449-456 ◽  
Author(s):  
Caroline CHAUVET ◽  
Brigitte BOIS-JOYEUX ◽  
Jean-Louis DANAN
Keyword(s):  
Gene Expression ◽  
Retinoic Acid ◽  
Hepg2 Cells ◽  
Transcriptional Activity ◽  
Cobalt Chloride ◽  
Retinoic Acid Receptor ◽  
Orphan Receptor ◽  
Human Hepatoma ◽  
Human Hepatoma Cells ◽  
Acid Receptor

The retinoic acid receptor-related orphan receptor α (RORα) is critically involved in many physiological functions in several organs. We find that the main RORα isoform in the mouse liver is the RORα4 isoform, in terms of both mRNA and protein levels, while the RORα1 isoform is less abundant. Because hypoxia is a major feature of liver physiology and pathology, we examined the effect of this stress on Rora gene expression and RORα transcriptional activity. HepG2 human hepatoma cells were cultured for 24h under normoxia (20% O2) or hypoxia (10, 2, and 0.1% O2) and the abundance of the Rora transcripts measured by Northern blot and semi-quantitative RT-PCR. Hypoxic HepG2 cells contained more Rora mRNA than controls. This was also observed in rat hepatocytes in primary culture. Cobalt chloride and desferrioxamine also increased the amount of Rora mRNA in HepG2 cells. It is likely that these treatments increase the amount of the RORα4 protein in HepG2 cells as evidenced by Western blotting in the case of desferrioxamine. Transient transfection experiments indicated that hypoxia, cobalt chloride, and desferrioxamine all stimulate RORα transcriptional activity in HepG2 cells. Hence, we believe that RORα participates in the control of gene transcription in hepatic cells and modulates gene expression in response to hypoxic stress.

scholarly journals Control of Gene Expression by the Retinoic Acid-Related Orphan Receptor Alpha in HepG2 Human Hepatoma Cells

PLoS ONE ◽  
2011 ◽  
Vol 6 (7) ◽  
pp. e22545 ◽  
Author(s):  
Caroline Chauvet ◽  
Amandine Vanhoutteghem ◽  
Christian Duhem ◽  
Gaëlle Saint-Auret ◽  
Brigitte Bois-Joyeux ◽  
...  
Keyword(s):  
Gene Expression ◽  
Retinoic Acid ◽  
Hepatoma Cells ◽  
Orphan Receptor ◽  
Human Hepatoma ◽  
Human Hepatoma Cells ◽  
Control Of Gene Expression ◽  
Receptor Alpha

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 The Environmental Light Influences the Circulatory Levels of Retinoic Acid and Associates with Hepatic Lipid Metabolism

Endocrinology ◽  
2008 ◽  
Vol 149 (12) ◽  
pp. 6336-6342 ◽  
Author(s):  
Wenqiang Pang ◽  
Chunying Li ◽  
Yue Zhao ◽  
Shiming Wang ◽  
Wei Dong ◽  
...  
Keyword(s):  
Gene Expression ◽  
Retinoic Acid ◽  
Adenosine Receptors ◽  
Light Exposure ◽  
Retinoic Acid Receptor ◽  
Hepatic Lipase ◽  
Mouse Retina ◽  
Acid Receptor ◽  
Hepatic Lipid ◽  
Environmental Light

Environmental light is involved in the regulation of photochemical reaction in mouse retina. It remains unclear whether light-mediated increase in all-trans retinoic acid (ATRA) synthesis in retina will result in altering the circulatory levels of ATRA and regulating downstream gene expression and physiological function. Here we showed circulatory levels of ATRA decreased in mice under constant darkness and elevated by light exposure. Fat gene pancreatic lipase-related protein 2 (mPlrp2) and its partner procolipase (mClps), but not hepatic lipase (mHl), activated in livers for responding to lack of light illuminating. Light-triggered alterations in circulatory ATRA levels regulated ecto-5′-nucleotidase gene expression by retinoic acid receptor retinoic acid receptor-α and modulated 5′-AMP levels in blood and were associated with mPlrp2 and mClps expression in the livers. Mice deficient in adenosine receptors displayed mPlrp2 and mClps expression in livers under 12-h light, 12-h dark cycles. Caffeine blocked adenosine receptors and induced hepatic mPlrp2 and mClps expression in wild-type mice. Mice activated in hepatic mPlrp2 and mClps expression lowered hepatic and serum lipid levels and markedly elevated circulatory levels of all-trans retinol. Our results suggest environmental light influence hepatic lipid homeostasis by light-modulated retinoic acid signaling associated with mPlrp2 and mClps gene expression in livers.

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