Transcriptional regulation of a Purkinje cell‐specific gene through a functional interaction between RORα and RAR

Mizutani, Takashi

doi:10.1111/j.1365-2443.1997.119gc0317.x

Cited by 37 publications

(18 citation statements)

References 46 publications

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“…RORa in the SCN or other brain regions is a retinoid-related orphan receptor recently incorporated to the molecular clock machinery (Sato et al, 2004), which activates BMAL1 transcription in a 24-h cycle. It has been shown that RORa-mediated transcription is activated synergistically by RAR in Pukinje cerebellar cells (Matsui, 1997), evidencing a functional interaction between RORa and RAR transcription factors. RARs operate as heterodimers with RXRs (Soprano et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Temporal patterns of lipoperoxidation and antioxidant enzymes are modified in the hippocampus of vitamin A‐deficient rats

et al. 2009

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Animals can adapt their behavior to predictable temporal fluctuations in the environment through both, memory-and-learning processes and an endogenous time-keeping mechanism. Hippocampus plays a key role in memory and learning and is especially susceptible to oxidative stress. In compensation, antioxidant enzymes activity, such as Catalase (CAT) and Glutathione peroxidase (GPx), has been detected in this brain region. Daily rhythms of antioxidant enzymes activitiy, as well as of glutathione and lipid peroxides levels, have been described in brain. Here, we investigate day/night variations in lipoperoxidation, CAT and GPx expression and activity, as well as the temporal fluctuations of two key components of the endogenous clock, BMAL1 and PER1, in the rat hippocampus and evaluate to which extent vitamin A deficiency may affect their amplitude or phase. Holtzman male rats from control, vitamin A-deficient and vitamin A-refed groups were sacrificed throughout a 24-h period. Daily levels of clock proteins, lipoperoxidation, CAT and GPx mRNA, protein, and activity, were determined in the rat hippocampus obtained every 4 or 5 h. Gene expression of RARα and RXRβ was also quantified in the hippocampus of the three groups of rats. Our results show significant daily variations of BMAL1 and PER1 protein expression. Rhythmic lipoperoxidation, CAT, and GPx, expression and activity, were also observed in the rat hippocampus. Vitamin A deficiency reduced RXRβ mRNA level, as well as the amplitude of BMAL1 and PER1 daily oscillation, phase-shifted the daily peak of lipoperoxidation, and had a differential effect on the oscillating CAT and GPx mRNA, protein, and activity. Learning how vitamin A deficiency affects the circadian gene expression in the hippocampus may have an impact on the neurobiology, nutritional and chronobiology fields, emphasizing for the first time the importance of nutritional factors, such as dietary micronutrients, in the regulation of circadian parameters in this brain memory-and-learning-related region.

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Section: Discussionmentioning

confidence: 99%

Temporal patterns of lipoperoxidation and antioxidant enzymes are modified in the hippocampus of vitamin A‐deficient rats

et al. 2009

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“…The suppression of ROR␣ by LXR␣ was also seen when a synthetic tk-Pcp2/RORELuc reporter was used. This reporter contains three copies of RORE derived from the Pcp2 gene (Matsui, 1997). As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Identification of Oxysterol 7α-Hydroxylase (Cyp7b1) as a Novel Retinoid-Related Orphan Receptor α (RORα) (NR1F1) Target Gene and a Functional Cross-Talk between RORα and Liver X Receptor (NR1H3)

Wada¹,

Kang²,

Angers³

et al. 2007

Mol Pharmacol

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The retinoid-related orphan receptors (RORs) and liver X receptors (LXRs) were postulated to have distinct functions. RORs play a role in tissue development and circadian rhythm, whereas LXRs are sterol sensors that affect lipid homeostasis. In this study, we revealed a novel function of ROR␣ (NR1F1) in regulating the oxysterol 7␣-hydroxylase (Cyp7b1), an enzyme critical for the homeostasis of cholesterol, bile acids, and oxysterols. The expression of Cyp7b1 gene was suppressed in the ROR␣ null (ROR␣ sg/sg ) mice, suggesting ROR␣ as a positive regulator of Cyp7b1. Promoter analysis established Cyp7b1 as a transcriptional target of ROR␣, and transfection of ROR␣ induced the expression of endogenous Cyp7b1 in the liver. Interestingly, Cyp7b1 regulation seemed to be ROR␣-specific, because ROR␥ had little effect. Reporter gene analysis showed that the activation of Cyp7b1 gene promoter by ROR␣ was suppressed by LXR␣ (NR1H3), whereas ROR␣ inhibited both the constitutive and ligand-dependent activities of LXR␣. The mutual suppression between ROR␣ and LXR was supported by the in vivo observation that loss of ROR␣ increased the expression of selected LXR target genes, leading to hepatic triglyceride accumulation. Likewise, mice deficient of LXR ␣ and ␤ isoforms showed activation of selected ROR␣ target genes. Our results have revealed a novel role for ROR␣ and a functional interplay between ROR␣ and LXR in regulating endo-and xenobiotic genes, which may have broad implications in metabolic homeostasis.

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“…ROREx5-tk-LUC containing five copies of RORE (TATATCAAGGT-CAT) was cloned into pTKLuc as described by Medvedev et al (24). mPCP-2x4-tk-LUC containing four copies of mouse Pcp-2 RORE (GT-TATAGTAACTGGGTCAGGGGACT) was cloned into pTKLuc as described by Matsui (25). The inserted sequences in the TKLuc clones were confirmed by big dye terminator version 3.1 cycle sequencing (ABI, Foster City, CA).…”

Section: Methodsmentioning

confidence: 99%

RORα Regulates the Expression of Genes Involved in Lipid Homeostasis in Skeletal Muscle Cells

Lau

Nixon

Parton

et al. 2004

Journal of Biological Chemistry

165

163

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The staggerer mice carry a deletion in the ROR␣ gene and have a prolonged humoral response, overproduce inflammatory cytokines, and are immunodeficient. Furthermore, the staggerer mice display lowered plasma apoA-I/-II, decreased plasma high density lipoprotein cholesterol and triglycerides, and develop hypo-␣-lipoproteinemia and atherosclerosis. However, relatively little is known about ROR␣ in the context of target tissues, target genes, and lipid homeostasis. For example, ROR␣ is abundantly expressed in skeletal muscle, a major mass peripheral tissue that accounts for ϳ40% of total body weight and 50% of energy expenditure. This lean tissue is a primary site of glucose disposal and fatty acid oxidation. Consequently, muscle has a significant role in insulin sensitivity, obesity, and the blood-lipid profile. In particular, the role of ROR␣ in skeletal muscle metabolism has not been investigated, and the contribution of skeletal muscle to the ROR؊/؊ phenotype has not been resolved. We utilize ectopic dominant negative ROR␣ expression in skeletal muscle cells to understand the regulatory role of RORs in this major mass peripheral tissue. Exogenous dominant negative ROR␣ expression in skeletal muscle cells represses the endogenous levels of ROR␣ and -␥ mRNAs and ROR-dependent gene expression. Moreover, we observed attenuated expression of many genes involved in lipid homeostasis. Furthermore, we show that the muscle carnitine palmitoyltransferase-1 and caveolin-3 promoters are directly regulated by ROR and coactivated by p300 and PGC-1. This study implicates RORs in the control of lipid homeostasis in skeletal muscle. In conclusion, we speculate that ROR agonists would increase fatty acid catabolism in muscle and suggest selective activators of ROR may have therapeutic utility in the treatment of obesity and atherosclerosis.Members of the nuclear hormone receptor (NR) 1 superfamily bind specific DNA elements and function as transcriptional regulators (1, 2). This group includes the "orphan NRs," which have no known ligands in the "classical sense." The orphan receptor, ROR/RZR (retinoic acid receptor-related orphan receptor), is closely related to Rev-erbA␣, RVR/Rev-erb␤/BD73, and the Drosophila orphan receptor, E75A, particularly in the DNA-binding domain and the putative ligand-binding domain. ROR, Rev-erbA␣, and RVR bind as monomers to an asymmetric (A/T) 6 RGGTCA motif. ROR functions as a constitutive transactivator of gene expression, and in contrast, Rev-erbA␣ and RVR do not activate transcription, mediate transcriptional repression, and can repress constitutive trans-activation from this motif by ROR␣ (3-9).Three ROR/RZR genes have been identified; ROR␣ encodes four ROR␣ isoforms ␣1, ␣2, ␣3, and RZR␣, which are alternatively spliced products of the ROR␣ gene and are predominantly expressed in blood, brain, skeletal muscle, and fat cells (8,10). ROR␤/RZR␤ is expressed specifically in the brain (11), and ROR␥ is found at high levels in skeletal muscle (12)(13)(14).Genetic studies have implicated ROR␣ in the ...

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Transcriptional regulation of a Purkinje cell‐specific gene through a functional interaction between RORα and RAR

Cited by 37 publications

References 46 publications

Temporal patterns of lipoperoxidation and antioxidant enzymes are modified in the hippocampus of vitamin A‐deficient rats

Temporal patterns of lipoperoxidation and antioxidant enzymes are modified in the hippocampus of vitamin A‐deficient rats

Identification of Oxysterol 7α-Hydroxylase (Cyp7b1) as a Novel Retinoid-Related Orphan Receptor α (RORα) (NR1F1) Target Gene and a Functional Cross-Talk between RORα and Liver X Receptor (NR1H3)

RORα Regulates the Expression of Genes Involved in Lipid Homeostasis in Skeletal Muscle Cells

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