Retinoic Acid Actions through Mammalian Nuclear Receptors

ArticleinChemical Reviews 114(1) · December 2013with19 Reads
DOI: 10.1021/cr400161b · Source: PubMed
Abstract
The retinoic acid receptors (RARs) and retinoid X receptors are among the most intensely studied nuclear hormone receptors. The six mammalian nuclear receptors for retinoids are encoded by distinct genes. Retinol oxidization to retinaldehyde occurs through enzymes in two classes, the cytosolic alcohol dehydrogenases (ADHs) and the microsomal short-chain dehydrogenases/reductases. There are various forms of retinoid-binding proteins in cells, some of which are in intracellular compartments while others carry the retinoids in the extracellular environment. Without knowing all the physical connections in these complexes, it is difficult to develop synthetic ligands that may act allosterically, by binding to one domain in the protein complex but inducing a functional change in another domain of the receptor. A better structural understanding of NR coactivators or corepressors is also required in the field. The dynamic expression of these retinoid receptors throughout different stages of development considerably suggests that we should now move beyond ligand binding.
    • "As an alternative approach, several laboratories developed retinoids that bind selectively to the RXR component of RXR/RAR heterodimers (known as rexinoids). As summarized in several review articles, the identity of endogenous RXR agonists remains controversial [26][27][28]. The first candidate for this role, a pan-agonist 9-cis-RA, was originally identified as endogenous RXR ligand through the reverse endocrinology approach (reviewed in [29] ). "
    [Show abstract] [Hide abstract] ABSTRACT: UAB30 is an RXR selective agonist that has been shown to have potential cancer chemopreventive properties. Due to high efficacy and low toxicity, it is currently being evaluated in human Phase I clinical trials by the National Cancer Institute. While UAB30 shows promise as a low toxicity chemopreventive drug, the mechanism of its action is not well understood. In this study, we investigated the effects of UAB30 on gene expression in human organotypic skin raft cultures and mouse epidermis. The results of this study indicate that treatment with UAB30 results in upregulation of genes responsible for the uptake and metabolism of all-trans-retinol to all-trans-retinoic acid (ATRA), the natural agonist of RAR nuclear receptors. Consistent with the increased expression of these genes, the steady-state levels of ATRA are elevated in human skin rafts. In ultraviolet B (UVB) irradiated mouse skin, the expression of ATRA target genes is found to be reduced. A reduced expression of ATRA sensitive genes is also observed in epidermis of mouse models of UVB-induced squamous cell carcinoma and basal cell carcinomas. However, treatment of mouse skin with UAB30 prior to UVB irradiation prevents the UVB-induced decrease in expression of some of the ATRA-responsive genes. Considering its positive effects on ATRA signaling in the epidermis and its low toxicity, UAB30 could be used as a chemoprophylactic agent in the treatment of non-melanoma skin cancer, particularly in organ transplant recipients and other high risk populations.
    Full-text · Article · Apr 2016
    • "Upon HSC activation , some retinoid contents are oxidized to retinaldehyde and to retinoic acid (RA), a finding that is supported by the fact that all-trans retinoic acid level is increased in activated stellate cells compared with pre-activated stellate cells, whereas the contents of retinyl ester and retinol decrease (Okuno et al, 1999; Radaeva et al, 2007; D'Ambrosio et al, 2011 ). The diverse effects of retinoids are primarily mediated by two families of nuclear receptors, retinoic acid receptor (RAR) and retinoid X receptor (RXR) (Huang et al, 2014 ). Albumin is an abundant multifunctional plasma protein synthesized primarily by liver cells (Evans, 2002). "
    [Show abstract] [Hide abstract] ABSTRACT: Activated hepatic stellate cells (HSCs) play a key role in liver fibrosis, and inactivating HSCs has been considered a promising therapeutic approach. We previously showed that albumin and its derivative designed for stellate cell-targeting, retinol-binding protein-albumin domain III fusion protein (referred to as R-III), inactivate cultured HSCs. Here, we investigated the mechanism of action of albumin/R-III in HSCs and examined the anti-fibrotic potential of R-III in vivo. R-III treatment and albumin expression downregulated retinoic acid (RA) signaling which was involved in HSC activation. RA receptor agonist and retinaldehyde dehydrogenase overexpression abolished the anti-fibrotic effect of R-III and albumin, respectively. R-III uptake into cultured HSCs was significantly decreased by siRNA-STRA6, and injected R-III was localized predominantly in HSCs in liver. Importantly, R-III administration reduced CCl4- and bile duct ligation-induced liver fibrosis. R-III also exhibited a preventive effect against CCl4-inducd liver fibrosis. These findings suggest that the anti-fibrotic effect of albumin/R-III is, at least in part, mediated by downregulation of RA signaling and that R-III is a good candidate as a novel anti-fibrotic drug. © 2015 The Authors. Published under the terms of the CC BY 4.0 license.
    Full-text · Article · Apr 2015
    • "difficulties in drug development and toxicity, as well as, the continued focus on the identification of natural ligands [10]. For example, the role of retinoid X receptors (RXRs) as heterodimeric partners of several members of the nuclear receptor family, including retinoic acid receptor (RAR), makes them promising drug targets; however, controversy still surrounds whether or not 9-cis-retinoic acid is its true endogenous ligand [11]. To bring attention to ONRs as prospective novel cancer drug targets , this article reviews general structural features and biological functions of ONRs and discusses some of the most promising candidates for therapeutic targeting in both prostate and breast cancers. "
    [Show abstract] [Hide abstract] ABSTRACT: Nuclear receptors (NRs), a family of 48 transcriptional factors, have been studied intensively for their roles in cancer development and progression. The presence of distinctive ligand binding sites capable of interacting with small molecules has made NRs attractive targets for developing cancer therapeutics. In particular, a number of drugs have been developed over the years to target human androgen- and estrogen receptors for the treatment of prostate cancer and breast cancer. In contrast, orphan nuclear receptors (ONRs), which in many cases lack known biological functions or ligands, are still largely under investigated. This review is a summary on ONRs that have been implicated in prostate and breast cancers, specifically retinoic acid-receptor-related orphan receptors (RORs), liver X receptors (LXRs), chicken ovalbumin upstream promoter transcription factors (COUP-TFs), estrogen related receptors (ERRs), nerve growth factor 1B-like receptors, and "dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1" (DAX1). Discovery and development of small molecules that can bind at various functional sites on these ONRs will help determine their biological functions. In addition, these molecules have the potential to act as prototypes for future drug development. Ultimately, the therapeutic value of targeting the ONRs may go well beyond prostate and breast cancers.
    Full-text · Article · Oct 2014
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