ReviewRetinoic acid signaling pathways in development and diseases
Graphical abstract
This graphical abstract represents the chemical structures of retinoic acid and several synthetic derivative retinoids, the use of these chemicals for probing mechanisms of developmental and cell biology, as well as their use as therapeutic agents for treating cancer and neurological disorder disease.
Introduction
Vitamin A or retinol is a fat-soluble compound derived from [beta]-carotene found in plants and retinyl esters from animal sources. It is stored in the liver and adipose tissue as retinyl esters and circulates in the blood in a protein complex containing retinol binding protein and transthyretin. Retinoic acid, the main derivative of vitamin A, binds to nuclear receptors, retinoic acid receptor (RAR) and retinoic X receptor (RXR) to regulation gene transcription. RA plays an important role in tissue development and differentiation. This review focuses on the role of RA in development and diseases, and the development of synthetic RA compounds for therapy and molecular imaging.
Section snippets
Synthesis, chemistry and analysis of RA
Retinoids comprise a group of compounds related to vitamin A, including its natural and synthetic analogues, which contain four isoprenoid units joined in a head-to-tail fashion. The basic structure of a retinoid consists of three parts: a trimethylated cyclohexene ring that is a bulky hydrophobic group, a conjugated tetraene side chain that serves as a linker unit, and a polar carbon–oxygen functional group, typically carboxylic acid as shown in Figure 1.
Retinoids are unstable due to the
Retinoid and carotenoid metabolism
Carotenoids or other retinoids are biochemically converted to retinoic acid (RA), which is essential for modulating a wide range of biological processes including development, differentiation, proliferation, and apoptosis. The bioconversion takes place successively (Fig. 3), first in the intestine, then the liver, and finally in target cells with the support of various binding proteins including cellular retinol-binding proteins (CRBPs), retinol-binding proteins (RBPs), and cellular retinoic
Genomic action of retinoids
Retinoids regulate various biological activities by binding RARs and RXRs. Ligand binding to the receptor causes conformational changes that modulate receptor complex function. In addition, these receptor complexes have a range of additional co-activators and co-repressors that modulate receptor activity. The composition of receptor complex is complicated by the presence of distinct subtypes and isoforms. Both RAR and RXR have three subtypes α, β, and γ, each with different isoforms. RARα and
RA signaling in normal development
The requirement for retinoids during embryogenesis has been long appreciated, since vitamin A is an essential dietary requirement. Yet for understanding mechanism, it is perplexing that loss of signaling or hyper-activation of the pathway can generate similar phenotypes. For example, excess RA causes many of the same embryonic developmental defects seen with vitamin A deficiency (VAD), which is why vitamin A intake levels should be monitored carefully during pregnancy. Because RA is
Retinoids in diseases
Though RA and it is analogs are essential for normal regulation of a wide range of biological processes, while deregulated retinoid signaling can contribute to serious diseases. In this section, we will briefly describe, how aberrant signaling of RA causes diseases, and how synthetic retinoids are used to treat some diseases.
Drug discovery and use of retinoids for treatment of diseases
As described above, several natural and synthetic retinoids have moved to clinical trials for various types of cancer, while several other classes of synthetic retinoids continue to be investigated at the pre-clinical level for anti-cancer activities. A major strategy to develop various synthetic retinoid derivatives with the potential to impart different biological activities is to systematically modify the hydrophobic, linker, or hydrophilic moieties of RA.
Recently, a series of acitretin
Retinoids in molecular imaging
Molecular imaging plays a very important role in the field of drug discovery. It provides a useful tool to track molecules and identify the molecular targets. Fortunately, an imageable RA derivative has been reported. The imageable compound 40 (Fig. 21) was developed by the conjugation of IRdye800cw and N-(aminohexyl0retinoicamide) [RA-NH(CH2)6NH2]. This near-infrared (NIR)-labeled agent was used for both in vitro and in vivo imaging studies. It can be used to detect multiple human cancer
Retinoids in stem cell biology and regenerative medicine
Retinoids regulates the stem cell differentiation via transcription activation. Retinoids are able to activate transcription by binding to the nuclear receptors RARα, RARβ, and RARγ. These RARs can form heterodimer with one of the RXRs and can bind with the DNA. This binding facilitates the activation of transcription of RA primary response genes, which are important for stem cell differentiation.114 Stem cells are unspecialized cells that have the ability to self-reproduce and differentiate
Conclusions
Retinoids comprise a group of natural and synthetic molecules, which regulate a variety of essential biological processes during normal development, help maintain homeostasis, and also mediate protection from diseases such as cancer and age-related disorders of the CNS. Genomic functions of the retinoids are mediated via their nuclear DNA-binding receptors, RARs and RXRs, which regulate gene transcription through recruitment of corepressors and coactivators. Retinoids also have notable
Acknowledgments
B.C.D. is thankful to University of Kansas Medical Center for startup funding. B.C.D. is supported by Grants from the NIH (AA020630 and AI093220). D.W.P. is supported by Grant from NIH (DK081579). T.E. is supported by Grants from the NIH (HL56182, HL111400) and NYSTEM (C028100).
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Both authors contributed equally to the paper.