Control of Gene Expression by Nuclear Retinoic Acid Receptors

Carrier, Marilyn; Rochette‐Egly, Cécile

doi:10.1002/9781118628003.ch5

Cited by 2 publications

(2 citation statements)

References 121 publications

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“…There is increasing interest in how micronutrients, such as vitamin A, play roles in the regulation of macronutrient metabolism. The major metabolite of vitamin A, alltrans-retinoic acid (RA), is known to regulate many physiological processes through its function as an activating ligand, or sometimes a repressive ligand, for nuclear retinoic acid receptors (RAR) including RARα, RARβ, and RARγ, each of which partner with retinoid X receptors (RXRα, RXRβ, and RXRγ), forming dimeric complexes that bind specifically to retinoic acid response elements (RARE) present in the promoter of target genes [1][2][3][4]. The canonical RARE consists of a core of two hexameric motifs of RGKTCA (where R and K represent any purine or pyrimidine, respectively), which are most often oriented as a direct repeat (DR) spaced by two and five nucleotides, although spacings of zero, one, and eight are also known, as well as inverted repeats (IR) separated by zero, three, and nine nucleotides [4].…”

Section: Introductionmentioning

confidence: 99%

Hepatocyte Nuclear Factor 4α (HNF4α) Plays a Controlling Role in Expression of the Retinoic Acid Receptor β (RARβ) Gene in Hepatocytes

Zolfaghari

Bonzo

Gonzalez

et al. 2023

IJMS

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HNF4α, a member of the nuclear receptor superfamily, regulates the genes involved in lipid and glucose metabolism. The expression of the RARβ gene in the liver of HNF4α knock-out mice was higher versus wildtype controls, whereas oppositely, RARβ promoter activity was 50% reduced by the overexpression of HNF4α in HepG2 cells, and treatment with retinoic acid (RA), a major metabolite of vitamin A, increased RARβ promoter activity 15-fold. The human RARβ2 promoter contains two DR5 and one DR8 binding motifs, as RA response elements (RARE) proximal to the transcription start site. While DR5 RARE1 was previously reported to be responsive to RARs but not to other nuclear receptors, we show here that mutation in DR5 RARE2 suppresses the promoter response to HNF4α and RARα/RXRα. Mutational analysis of ligand-binding pocket amino acids shown to be critical for fatty acid (FA) binding indicated that RA may interfere with interactions of FA carboxylic acid headgroups with side chains of S190 and R235, and the aliphatic group with I355. These results could explain the partial suppression of HNF4α transcriptional activation toward gene promoters that lack RARE, including APOC3 and CYP2C9, while conversely, HNF4α may bind to RARE sequences in the promoter of the genes such as CYP26A1 and RARα, activating these genes in the presence of RA. Thus, RA could act as either an antagonist towards HNF4α in genes lacking RAREs, or as an agonist for RARE-containing genes. Overall, RA may interfere with the function of HNF4α and deregulate HNF4α targets genes, including the genes important for lipid and glucose metabolism.

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Section: Introductionmentioning

confidence: 99%

Hepatocyte Nuclear Factor 4α (HNF4α) Plays a Controlling Role in Expression of the Retinoic Acid Receptor β (RARβ) Gene in Hepatocytes

Zolfaghari

Bonzo

Gonzalez

et al. 2023

IJMS

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“…Retinoic acid (RA), a major active metabolite of vitamin A, functions as a pan-agonist ligand of nuclear retinoic acid receptors (RARα, β, and γ), which partner with retinoid X receptors (RXRα, β, and γ) and bind specifically to retinoic acid response elements (RARE) in target genes [1][2][3][4]. The canonical RARE consists of a core of two hexameric motifs of PuG(G/T)TCA(X) n PuG(G/T)TCA, generally oriented as a direct repeat (DR) spaced by two or five nucleotides (called DR2 or DR5).…”

Section: Introductionmentioning

confidence: 99%

CYP26A1 gene promoter is a useful tool for reporting RAR-mediated retinoid activity

Zolfaghari

Mattie

Wei

et al. 2019

Analytical Biochemistry

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Of numerous genes regulated by retinoic acid (RA), CYP26A1 is the most inducible gene by RA. In this study, we have used a shortened construct form, E4, of the CYP26A1 gene promoter, in a promoter-less vector with either luciferase or red fluorescent protein (RFP) as the reporter gene and have tested its responses to retinoids in transfected HepG2 and HEK293T cells. The promoter responded linearly to a wide concentration range of RA in cells cotransfected with retinoic acid receptors. It also responded quantitatively to retinol and other retinoids. An isolated clonal line of HEK293T cells permanently transfected with the promoter driving the expression of RFP responded to both RA and retinol, and the responses could be measured by fluorescence microscopy and flow cytometry. The promoter was used to assess the retinoid activity of 3 novel synthetic retinoid analogues, as well as of the intact serum samples of rats. Among the synthetic retinoid analogues tested, EC23 is more potent than RA at lower concentrations and was more stable than RA. The retinoid activities could be measured in control rat serum samples and were increased in the serum of RA-treated rats. This system offers a biologically-based alternative to massbased retinoid analysis.

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Control of Gene Expression by Nuclear Retinoic Acid Receptors

Cited by 2 publications

References 121 publications

Hepatocyte Nuclear Factor 4α (HNF4α) Plays a Controlling Role in Expression of the Retinoic Acid Receptor β (RARβ) Gene in Hepatocytes

Hepatocyte Nuclear Factor 4α (HNF4α) Plays a Controlling Role in Expression of the Retinoic Acid Receptor β (RARβ) Gene in Hepatocytes

CYP26A1 gene promoter is a useful tool for reporting RAR-mediated retinoid activity

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