Retinoids are a class of chemical compounds that include active metabolites of vitamin A (retinol) as well as a diverse array of synthetic derivatives. Vitamin A is required for normal embryonic development, epithelial homeostasis, maintainance of reproductive capacity, and functioning of the visual cycle (1). Additionally, retinoids have been shown to modulate a wide variety of cellular processes, including proliferation, differentiation, homeostasis, and malignant transformation (for reviews see refs. 2-5). Retinoids also act pharmacologically to restore regulation of differentiation and growth in certain prema-lignant and malignant cells in vitro and in vivo (6,7). Consequently, retinoids are under study as therapeutic and chemopreventive agents for a variety of cancers (see refs. 8-10 for reviews). Retinoids are also potent drugs for the treatment of severe cystic acne, psoriasis, and several other dermatologic disorders (11).
At least 24 different retinoid binding proteins have been identified to date. With the exception of specialized proteins in visual tissue, these proteins fall into three general classes:
From: Antiangiogenic Agents in Cancer Therapy Edited by: B. A. Teicher © Humana Press Inc., Totowa, NJ
Early attempts at understanding the molecular basis of retinoid action were directed toward two families of cytosolic retinoid binding proteins, the cellular retinol-binding proteins (CRBPs) and cellular retinoic acid binding proteins (CRABPs). The cDNAs for these proteins have been cloned, and it has been shown that there are at least two CRABP proteins and two CRBP proteins, each encoded from a different gene (13). These proteins have distinct spacial and temporal distributions in developing mouse and chick embryos (14-17); however, double knockout mice lacking expression of both CRAB PI and CRABPII develop normally and have almost no observable defects (18). Although the lack of a knockout phenotype in these mice is difficult to explain, other evidence suggests that CRABP may either act as a sink for RA or enhance its metabolism, effectively reducing the amount of free RA in a cell (19,20). Considered together, these findings suggest an important but auxilliary role for CRABPs and CRBPs in retinoid signaling.
Following the discovery and cloning of CRABPs and CRBPs, another class of retinoid binding proteins, the nuclear retinoid receptors, was discovered (21,22). It is now believed that retinoids exert their effects primarily through these proteins. The nuclear retinoid receptors comprise two families of ligand-dependent, DNA-binding, transcriptional transactivators, the retinoic acid receptors (RARs) and retinoid X receptors (RXRs), both members of the nuclear hormone receptor superfamily (3,5,23,24). There are three members (types) of each family of retinoid receptors, designated, RARa, b, and g and RXRa, b, and g, each encoded by different genes. Each gene can generate multiple mRNA splice variants encoding receptor isoforms with unique amino-termini (23, 25, and references therein).
RARs are activated by all-trans retinoic acid (tRA) and its 9-cis isomer (9C-RA), whereas RXRs are only activated by 9C-RA. Retinoid receptors bind DNA and activate transcription primarily as RAR/RXR heterodimers (23; Fig. 1). Several in vitro studies demonstrated that ligand binding of both the RAR and RXR partner resulted in enhanced transcriptional activation compared to that caused by liganding of either partner alone (26-28). This, along with evidence from studies of retinoid receptor knockout mice, strongly suggests that RAR/ RXR heterodimers transduce the retinoid signal in vivo (3,5,29).
The RAR and RXR proteins share a similar domain structure with other members of the steroid/thyroid hormone receptor superfamily, consisting of six regions designated A-F in the case of RARs and five regions A-E in the case of RXRs. The A/B domain contains a transcriptional activation function (AF-1) that acts in a promoter context- and receptor type-specific fashion and accounts for the constitutive transcriptional activity of RARs and RXRs (30,31). The AF-1 of one of the RARs, RARa, can be phosphorylated by a component of the basal transcriptional machinery, resulting in enhanced transriptional transactivation (32). The other transcriptional activation function (AF-2) is found within the highly conserved E region, which also contains the ligand-binding and dimerization domains (30,31,33; see refs. 3 and 24 for reviews). Ligand binding brings about conformational alterations in the receptors, of which one consequence is the exposure of an interacting surface contained within the AF-2 (34,35). This surface contacts transcriptional intermediary factors (also called coactivators), which are thought to form a bridge between the RAR/RXR heterodimer and the basal transcriptional machinery and to establish contacts with proteins involved in chromatin remodeling (36-41). Another consequence of ligand binding is the dissociation of the RAR partner with corepressor proteins, also called silencing mediators, which repress transcription when bound to unliganded RARs (42-44).
The C region contains a zinc finger DNA-binding motif and is the most highly conserved domain between the different steroid receptor family members as well as between
members of the RAR and RXR classes. C is-acting DNA to which the C domains bind are termed RA response elements (RARES), and they all share a paired repeat motif of the sequence PuG(G/T)TCA (Pu = purine) that can vary in spacing and orientation. There is a growing list of genes that contain RAREs, including both genes for which transcriptional modulation by RA is an immediate effect and genes for which it is delayed (4).
The various RAR and RXR types and isoforms are highly conserved in evolution, and display distinct spatio-temporal expression patterns in developing organisms and in the adult, which suggests that each receptor exerts some distinct physiological functions (reviewed in ref. 5). In addition to RARs, the RXRs can dimerize with several other steroid hormone receptor family members (2,24,45-47, and references therein). Upon heterodimerization, RXRs have been shown to modulate the DNA-binding and AFs of these receptors in vitro and in transfected cells. Recent studies provide evidence that ligand-binding of the RXR partner can also enhance the transcriptional activity of several of these receptors in a similar manner to RARs (48,49). Thus, RXRs, and by extension 9C-RA, are likely to play a key role in the control of several signaling pathways.
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