Nuclear retinoid receptors

Retinoids (i.e., tretinoin and tazarotene) mediate cellular responses primarily through activation of nuclear retinoid receptors [rr]. There are two types of nuclear retinoic acid receptors the retinoic acid receptors (RARs) and the retinoid X receptors. Each type of receptor contains three receptor subtypes alpha, beta, and gamma [rr, 11]. Among the commonly prescribed retinoids, tretinoin activates the RARs alpha, beta, and gamma directly, and the retinoid X receptors indirectly (through conversion of tretinoin to 9-cis-retinoic acid) [rr, 13]. Conversely,... 

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. 

Retinoid Hormones Retinoids are potent hormones that regulate the growth, survival, and differentiation of cells via nuclear retinoid receptors. The prohormone retinol is synthesized from vitamin A, primarily in liver (see Fig. 10-21), and many tissues convert retinol to the hormone retinoic acid (RA). 

All tissues are retinoid targets, as all cell types have at least one form of nuclear retinoid receptor. In adults, the most significant targets include cornea, skin, epithelia of the lungs and trachea, and the immune system. RA regulates the synthesis of proteins essential for growth or differentiation. Excessive vitamin A can cause birth defects, and pregnant women are advised not to use the retinoid creams that have been developed for treatment of severe acne. 

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... 

Rowe A and Brickell P (1993) Current status review the nuclear retinoid receptors. International Journal of Experimental Pathology 74,117-26. 

Bollag, W., Isnardi, L., Jablonska, S., Klaus, M., Majewski, S., Pirson, W. and Toma, S. (1997) Links between pharmacological properties of retinoids and nuclear retinoid receptors. International Journal of Cancer, 70, 470-472. 

J. Bastien, C. Rochette-Egly, Nuclear retinoid receptors and the transcription of retinoid-target genes, Gene 2004, 328,1-16. 

Retinoids which have been examined for their affinities for the nuclear retinoic acid receptors are included in Table 1.1 and are labelled as indicated. There appears to exist a good correlation between the activity of retinoids by standard biological assays and that reflected in the abihties of these retinoids to bind to or activate the nuclear retinoid receptors [81,84,86-88] ... 

Table 1.1. RETINOIDS STUDIED FOR ABILITY TO ACTIVATE OR BIND TO NUCLEAR RETINOID RECEPTORS...

The potent retinoids TTNPB (Rl), TTNN (R18), and (R12) all bind strongly to nuclear retinoid receptors [81,84,87,88]. TTNN binds poorly, however, with RARa [81,84,88]. (R12) binds with greatest affinity to all three RAR types compared with all other retinoids tested [81,84,88]. Confficting data on the affinity of TTNPB for RARa and RAR is apparent [81,88]. 

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]. ... 

Nuclear-retinoid receptors provide a mechanism of retinoid action, but most likely where expressed, the cytosolic cellular retinoic acid-binding proteins (CRABPs) also affect the ability of retinoids to initiate biological signals (1,2). holo-CBlABP I sequesters retinoic acid (RA) with a value that may be <1 nM, and serves as a high-affinity 2 nM), efficient substrate of RA... 

The understanding of the mechanism by which retinoids modulate gene expression implies that retinoids activate a signal-transduction pathway in which nuclear-retinoid receptors, which are members of the steroid hormone-receptor superfamily, play a pivotal role (14,16,18-22). Like other members of this family, the retinoid receptors are ligand-activated, DNA-binding transacting, transcription-modulating proteins. Two types of receptor have been identified retinoic acid receptors (RARs) and retinoid X receptors (RXRs) each type includes three subtypes of RAR (a, p, and y) and of RXR (a, P, and y) with distinct ammo- and carboxy-terminal domains. RXR-RAR... 

As shown in Figure 11.5, there are two families of nuclear retinoid receptors the retinoic acid receptors (RAR) bind A -trans-Ktmoic acid or 9- r-retinoic acid and the retinoid X receptors (RXR) bind 9- r-retinoic acid. Retinoic acid is involved in the regulation of a wide variety of genes there are three types of activated retinoid receptor dimers, which bind to different response elements on DNA ... 

Although not strictly a method of retinoid chromatography, high-performance size-exclusion chromatography can be used to assess the binding affinities of synthetic retinoid ligands for the nuclear retinoid receptor proteins RAR and RXR (162,163). 

Kurlandsky SB, Xiao JH, Duell EA, Voorhees JJ, Fisher GJ (1994) Biological activity of dW-trans retinol requires metabolic conversion to A -trans retinoic acid and is mediated through activation of nuclear retinoid receptors in human keratinocytes. J Biol Chem 269 32821-32827... 

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