Retinoid receptors functions

The retinoid receptors function as dimers. Thus, the RAR subtypes heterodimerize with the RXR subtypes. The RXRs also can homodimerize or heterodimerize with the vitamin D, thyroid hormone, and the orphan receptors. The receptor dimers act either directly or indirectly to regulate gene function. The dimers bind directly to retinoid response elements (RAREs and RXREs). These response elements (REs) are specific sequences in the promoter regions of retinoid-responsive genes, which typically consist of two conserved sequences of six nucleotide bases that are separated by discrete numbers of bases. For example, RXR-RAR dimers bind to RAREs which are direct repeats of AGGTCA separated by five (synthetic DR-5 sequence) or two (synthetic DR-2) nucleotides or are palindromic, inverted, or more complex in structure [6]. 

A most important function of vitamin A is in the control of cell differentiation and mrnover. PsA-trans-retinoic acid and 9-cw-retinoic acid (Figure 45-1) regulate growth, development, and tissue differentiation they have different actions in different tissues. Like the steroid hormones and vitamin D, retinoic acid binds to nuclear receptors that bind to response elements of DNA and regulate the transcription of specific genes. There are two families of nuclear retinoid receptors the retinoic acid receptors (RARs) bind all-rrijw-retinoic acid or 9-c -retinoic acid, and the retinoid X receptors (RXRs) bind 9-cw-retinoic acid. 

Upregulation of retinoid receptor expression and function by provitamin A carotenoids may play a role in mediating the growth inhibitory effects of retinoids in cancer cells (Lian et al. 2006, Prakash et al. 2004). However, it is unclear if non-provitamin A carotenoids and their metabolites may act... 

Vitamin A absorbs UV light between 300 and 350 nm. After acute exposure to UVA or UVB a dose-dependent decrease of vitamin A was shown in mouse59 and humans.84 UV irradiation markedly reduced mRNA and protein of the nuclear retinoid receptors RARy and RXRa in humans and led to a near loss of retinoic acid induction of the RAR/RXR target genes and the cellular retinoic acid binding protein II thus effectively causing additionally a functional vitamin A deficiency.85... 

CRABP (1) and CRABP (11) function to transport retinoic acid into the nucleus for binding to retinoid receptors. CRABP(ll), with retinoic acid bound, also interacts directly with the liganded RAR-RXR heterodimer bound to hormone response elements on DNA and enhances the activity of the nuclear receptor (Section2.3.2.1 Delvaetal., 1999). 

These retinoid receptors must form dimers before they interact with RAREs. RARs must form heterodimers with RXR.S, whereas RXRs may also form homodimers. It appears that the RAREs for the homodimers differ from those for the heterodimers. This implies that they may activate different sets of genes. RXRs also form hetcrodimers with thyroid hormone receptors and vitamin O receptois. increasing their affinity for DNA. Several enzymes whose expression depends on RXR have been found. The available experimental data provide convincing evidence that these proteins are, in fact, nuclear receptors belonging to the steroid/thyroid hormone superfamily. They mediate important aspects of vitamin A function. The existence of proteins that specifically bind retinoic acid substantiates the implication of retinoic acid as a physiological form of vitamin A. 

Alitretinoin binds to and activates all known intracellular retinoid receptor substrates. Once activated, these receptors function as transcription factors that regulate the expression of genes that control the process of cellular differentiation and proliferation of both non-rial and neoplastic cells. Alitretinoin is indicated in the topical treatment of AIDS-related Kaposi sarcoma (KS). 

The presence of a carboxyl terminal group is necessary for binding to CRABP and for retinoid activity [2]. However, comparison of other retinoid structural features shows a lack of correlation between retinoid potency and affinity for CRABP. Some potent retinoids do not bind to CRABP but do bind to nuclear retinoid receptors such as the RARs [146-149]. One such retinoid has been reported to be equally or more potent than RA but has lower affinity for RARs than RA [149]. It has been suggested that the reason for this apparent anomaly may be that the potency of RA is reduced because of its ability to bind to endogenous CRABP. It appears, therefore, that one of the functions of CRABP may be to regulate the amount of intracellular-active RA and thus control quantitatively the intensity of biological effects [149]. ... 

Aside from the well-recognized role of retinoids in the chemistry of vision,they bind to, and therefore activate, up to six intracellular retinoid receptors (the RARs and RXRs)J" In doing so they serve as modulators of nuclear transcription, which impacts numerous cellular events (e.g., reproduction, immune function, and development). Such actions have consequences for treatment of certain cancers, including leukemia, melanoma, Kaposi s sarcoma, and squamous cell carcinoma. Several approaches to both natural and unnatural retinoids, which make use of a Pd(0)-induced vinyl-vinyl cross-coupling, have appeared over the last decade, with extensive woik ongoing given the connection to oncology. 

A number of other nuclear receptors have also been shown to bind and be activated by retinoids. For example, testicular receptor 4 (TR4) has recently been suggested to be a retinoid receptor, because the binding of both retinol and RA can induce conformational changes of TR4 leading to the activation of this receptor (Zhou et al. 2011). TR4 can either function as homodimer or heterodimerize with testicular receptor 2 (TR2) to function in spermatogenesis, hpid and hpoprotein regulation, and central nervous system development (Zhou et al. 2011). However, additional experiments are required to reveal the physiological and developmental implications of the activation of TR4 by retinoids, such as RA (Zhou et al. 2011). 

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