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

Chauvet, Caroline; Bois-Joyeux, Brigitte; Danan, Jean‐Louis

doi:10.1042/bj20011558

Cited by 47 publications

(44 citation statements)

References 50 publications

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“…These results suggest that RORA is expressed in normal human tissues and RORA1 and RORA4 are the main transcripts of the RORA gene. These are consistent with the results obtained from other research groups (Lau et al, 1999;Chauvet et al, 2002;Migita et al, 2004).…”

Section: Resultssupporting

confidence: 83%

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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: Resultssupporting

confidence: 83%

“…As shown in Figure 6, MCF12F cells were transfected with pcDNA3-RORA4, as RORA4 is one of the predominant isoforms of RORA expressed (Chauvet et al, 2002) and RORA1 is more specifically produced in the central nervous system (Matysiak-Scholze and Nehls, 1997). The cell number Figure 6).…”

Section: Overexpression Of Rora Inhibits Cellular Growthmentioning

confidence: 99%

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

et al. 2006

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“…The different time course of ROR␣ expression suggests that ROR␣ is involved in different pathways in neurons and in astrocytes. The induction of ROR␣ transcripts after hypoxia has been reported in various cell lines including human aortic smooth muscle cells, endothelial cells, and HepG2 cells (Besnard et al, 2002;Chauvet et al, 2002Chauvet et al, , 2004Miki et al, 2004;Kim et al, 2008). The induction of ROR␣ was attributed to an HRE (hypoxia response element) in the Rora promoter (Chauvet et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…The transcription factor retinoid-related orphan receptor-␣ (ROR␣) has been shown also to be a target of HIF-1␣ (Chauvet et al, 2004;Miki et al, 2004). Moreover, ROR␣ expression is increased by hypoxia in various cell lines (Chauvet et al, 2002;Miki et al, 2004;Kim et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Cell-Autonomous and Non-Cell-Autonomous Neuroprotective Functions of RORα in Neurons and Astrocytes during Hypoxia

Jolly¹,

Journiac²,

Naudet³

et al. 2011

J. Neurosci.

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There is increasing evidence to suggest that the neuronal response to hypoxia is regulated through their interactions with astrocytes. However, the hypoxia-induced molecular mechanisms within astrocytes which influence neuronal death have yet to be characterized. In this study, we investigated the roles of the nuclear receptor ROR␣ (retinoid-related orphan receptor-␣) respectively in neurons and astrocytes during hypoxia using cultures and cocultures of neurons and astrocytes obtained from ROR␣-deficient mice. We found that loss of ROR␣ function in neuronal cultures increases neuronal death after hypoxia, suggesting a cell-autonomous neuroprotective effect of ROR␣. Moreover, wild-type neurons cocultured with ROR␣-deficient astrocytes are characterized by a higher death rate after hypoxia than neurons cocultured with wild-type astrocytes, suggesting that ROR␣ also has a non-cell-autonomous action. By using cocultures of neurons and astrocytes of different genotypes, we showed that this neuroprotective effect of ROR␣ in astrocytes is additive to its effect in neurons, and is mediated in part by cell-to-cell interactions between neurons and astrocytes. We also found that ROR␣ is upregulated by hypoxia in both neurons and astrocytes. Furthermore, our data showed that ROR␣ does not alter oxidative mechanisms during hypoxia but regulates hypoxic inducible factor 1␣ (HIF-1␣) expression, a major regulator of hypoxia sensing, in a cell-specific manner. Indeed, the neuroprotective function of ROR␣ in astrocytes correlates with a downregulation of HIF-1␣ selectively in these cells. Altogether, our results show that ROR␣ is a key molecular player in hypoxia, protecting neurons through its dual action in neurons and astrocytes.

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“…ROR sg/sg mice have decreased ROR␣ expression in all tissues (20,26) and a phenotype similar to the engineered ROR␣-KO mice (42). The truncated ROR␣ protein was unstable and not detectable (5,13).…”

Section: Methodsmentioning

confidence: 99%

The nuclear retinoid-related orphan receptor-α regulates adipose tissue glyceroneogenesis in addition to hepatic gluconeogenesis

Kadiri

Monnier

Ganbold

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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Circadian rhythms have an essential role in feeding behavior and metabolism. ROR␣ is a nuclear receptor involved in the interface of the circadian system and metabolism. The adipocyte glyceroneogenesis pathway derives free fatty acids (FFA) liberated by lipolysis to reesterification into triglycerides, thus regulating FFA homeostasis and fat mass. Glyceroneogenesis shares with hepatic gluconeogenesis the key enzyme phosphoenolpyruvate carboxykinase c (PEPCKc), whose gene is a ROR␣ target in the liver. ROR␣-deficient mice (staggerer, ROR sg/sg ) have been shown to exhibit a lean phenotype and fasting hypoglycemia for unsolved reasons. In the present study, we investigated whether adipocyte glyceroneogenesis might also be a target pathway of ROR␣, and we further evaluated the role of ROR␣ in hepatocyte gluconeogenesis. In vivo investigations comparing ROR sg/sg mice with their wild-type (WT) littermates under fasting conditions demonstrated that, in the absence of ROR␣, the release of FFA into the bloodstream was altered and the rise in glycemia in response to pyruvate reduced. The functional analysis of each pathway, performed in adipose tissue or liver explants, confirmed the impairment of adipocyte glyceroneogenesis and liver gluconeogenesis in the ROR sg/sg mice; these reductions of FFA reesterification or glucose production were associated with decreases in PEPCKc mRNA and protein levels. Treatment of explants with ROR␣ agonist or antagonist enhanced or inhibited these pathways, respectively, in tissues isolated from WT but not ROR sg/sg mice. Our results indicated that both adipocyte glyceroneogenesis and hepatocyte gluconeogenesis were regulated by ROR␣. This study demonstrates the physiological function of ROR␣ in regulating both glucose and FFA homeostasis. glyceroneogenesis; phosphoenolpyruvate carboxykinase c; nuclear retinoid-related orphan receptor-␣; adipose tissue RETINOID-RELATED ORPHAN RECEPTORS (RORs) are members of the nuclear receptor family. The ROR family comprises three members: ROR␣ (NR1F1), ROR␤ (NR1F2), and ROR␥ (NR1F3), with ROR␣ being the most abundant isoform present in the adipose tissue (18). RORs regulate gene transcription by binding to specific DNA response elements (RORE) consisting of the consensus RGGTCA core motif. Reciprocally, the nuclear receptor Rev-erb␣ (NR1D1) acts as a transcriptional repressor by competing with RORs for RORE binding and thereby antagonizes ROR action. Indeed, both receptors are often coexpressed in the same tissues (14).ROR␣ and Rev-erb␣ are involved in many pathways implicated in various physiological functions, including immune function, circadian rhythms, and metabolism. They appear to be pivotal players at the interface between the circadian system and metabolism (49). Among the direct target genes of ROR␣ and Rev-erb␣ are several clock genes such as Bmal1, thus ensuring a fine tuning of circadian rhythms, as well as some metabolic genes involved in the control of cholesterol and bile acid metabolism (11, 29) apolipoprotein synthesis (39), lipogene...

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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

Cited by 47 publications

References 50 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

Cell-Autonomous and Non-Cell-Autonomous Neuroprotective Functions of RORα in Neurons and Astrocytes during Hypoxia

The nuclear retinoid-related orphan receptor-α regulates adipose tissue glyceroneogenesis in addition to hepatic gluconeogenesis

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