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Retinoic acid and the genetics of positional information
Published in David M. Gardiner, Regenerative Engineering and Developmental Biology, 2017
Malcolm Maden, David Chambers, James Monaghan
The RARs are present in the nucleus of cells as heterodimers, with the retinoid X receptors (RXRs) bound to a DNA sequence known as an RA response element (RARE) (Figure 7.4). There are three RARs known as RARα, RARβ, and RARγ (and multiple isoforms of each subtype) and three RXRs (RXRα, RXRβ, and RXRγ and their multiple isoforms), and so, there are multiple heterodimeric combinations of a RAR and a RXR that can exist in the nucleus. In the newt, there are at least six isoforms of the RARs: α1, α2, δ1a, δ1b, δ2 (the newt δ is equivalent to the mammalian γ), and β2. When RA binds the heterodimer composed of one RAR and one RXR, it is transcriptionally activated. Only the RAR/RXR heterodimer is shown in Figure 7.4 for simplicity, but there is a multi-protein corepressor complex that disassociates on RA binding and a coactivator complex that is recruited in order to acetylate and methylate histones to decompact the chromatin (Carrier and Rochette-Egly 2015; Wei 2015).
Retinoic acid as a teratogen: IX-Induction of fetal skeletal anomalies and alteration in the utero-placental expression pattern of EGFR during mice development
Published in Egyptian Journal of Basic and Applied Sciences, 2022
Ahmed Said, Abdel-Rahman S. Sultan, Reda A. Ali, Mohsen A. Moustafa
Retinoic acid (RA), a bioactive vitamin A metabolite, is a signaling molecule, tightly regulated during embryogenesis; indispensable for the formation of many organs, including body axis, spinal cord, eyes, limbs, heart, and kidneys [7–10]. RA is also a valuable compound in the therapy of cystic acne among other numerous dermatologic disorders [11–13]. In target cells, RA acts as a ligand for nuclear retinoic acid receptors (RARs), which form heterodimers with retinoid X receptors (RXRs). The complex binds to a regulatory DNA segment, the retinoic acid response element (RARE), to control transcription of RA target genes. Maternal retinoic acid excess or deficiency during pregnancy cause abnormalities both in human infants [9,14] and in rodents [15], indicating that retinoic acid levels must be within a specific range for normal development [16]. Rat fetuses in mothers reared on vitamin A-deficient diets demonstrate an array of anomalies collectively known as ‘fetal vitamin A deficiency’ (VAD) syndrome, which comprises hind-brain, eye, ear, heart, lung, diaphragm, kidney, testis, limb and skeletal defects [17]. Similarly, mice with compound null mutations of RA nuclear receptors [18,19] and RA-synthesizing enzymes have malformations resembling the VAD syndrome [20]. Notably, excess vitamin A/RA in humans and animal models causes malformations resembling the fetal VAD syndrome [21,22].
Genetic polymorphisms of PPAR genes and human cancers: evidence for gene–environment interactions
Published in Journal of Environmental Science and Health, Part C, 2019
Peroxisomes are single membrane-bound organelles, with a granular matrix, that are found in different types of animal and plant cells. Peroxisomes host diverse metabolic functions, including α- and β-oxidation of fatty acids, bile acid and phospholipid biosynthesis, cholesterol biotransformation, and detoxification of oxygen-based reactive metabolites.1 Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear transcription factors that acquired their name when the first discovered receptor in this group was shown to mediate peroxisome proliferation in rodents upon chemical exposure. PPARs are currently associated with a much wider range of systemic and cellular functions beyond their reported role when first discovered (Figure 1). These receptors mainly regulate cellular functions and gene expression based on an activation by a ligand. Following binding by an agonist, PPARs release histone deacetylase (HDAC) co-repressors, hence enabling their hetero-dimerization with the retinoid X receptor (RXR). The RNA Polymerase II and the rest of the transcription machinery are then recruited to the forming complex in order to bind to PPAR responsive regulatory elements, known as direct repeat elements.2,3 This mechanism underlies PPARs’ involvement in the transcription of target genes that contribute to metabolism of hormones, carbohydrates, various lipids and general adipogenesis, as well as inflammatory responses, cell death, cell proliferation, and oncogenic signaling.3 Whether a PPAR functions as an oncogene or as a tumor suppressor gene is still uncertain. This is mainly due to the complexity of the pathways that are regulated by PPARs, and their tendency to be altered in tumorigenesis in various types of cancer. The fact that PPARs are activated by both endogenous ligands and xenobiotics underlies their potential ability to regulate tumorigenesis dependently or independently of an environmental exposure.4 In addition, their role in cancer-associated biological processes, including apoptosis, cell proliferation, and terminal differentiation, is still under research, with controversial results showing in many published reports.3 Similarly, several studies and systematic reviews investigating an association between PPARs’ polymorphisms and cancer risk are also showing inconsistencies.5–7 However, data on gene–environment interactions potentially underlying these associations remains largely unexamined despite the fact that some studies have suggested PPARs as important factors at the interface between genes and the environment.8 This review aims at comprehensively examining the existing evidence of gene–environment interaction (GxE) underlying PPARs genetic polymorphisms and their association with cancer risk.