RA response elements

Figure 2 A model for RAR/RXR acting in concert with coactivator or corepressor complex for gene activation or silencing. In the presence of ligands (+RA), the holo-receptor pair binds to the RA response element (RARE) and recruits coactivator complex, which encodes histone acetyl transferase (HAT) activity. HAT acetylates histone proteins, opens up the chromatin, and allows the transcription machinery to act on the promoter for active gene transcription. In the absence of ligands (—RA), the apo-receptor pair binds to the RARE and recruits corepressor that encodes histone deacetylase (HDAC) activity, inducing histone deacetylation, chromatin condensation, and gene silencing.

The most important natural retinoids are retinyl esters, retinol, and retinoic acid (RA). In the all-trans form, RA is the ligand for the nuclear RA receptors RAR- , RAR- ], and RAR- " in the 9-cis form, it is the ligand for the retinoid X receptors (RXRs), which form heterodimers with RARs to form the transcriptionally active complex that binds to RA response elements of target genes, as well as with the RARs see (2) for details and references). In the past, retinyl esters and retinol have been used for treating embryos (3,4) their effects on the developmental pattern probably depend on conversion to RA, although some other natural metabolites, such as 4-oxo-RA, may also be directly active (5). Most recent studies have used RA (mainly in the all-tra 5 form) for experimental purposes. 

As discussed below, a recent analysis of the IFN-y promoter revealed an RA response element, and promoter-reporter constructs responded positively to RA [17]. It is unknown, however, whether the IFN-y gene is a primary target of RA in vivo. At present, the physiological regulation of IFN-y production during VA deficiency and by RA is not understood. 

Besides the role of retinoids in host immune defenses to viral infections (see [6] for review), retinoids may also affect virus replication. Angulo et al. [44] characterized three RA response elements in the promoter region of human cytomegalovirus (hCMV) and demonstrated the necessity for RAR and RXR in the viral promoter s positive response to RA. In contrast, the replication of herpes simplex virus-1 (HSV-1) in cultured Vero cells was inhibited by isomers of RA, but not retinol inhibition occurred without evident induction of IFN-a or IFN-p gene expression [45]. RA also protected HL-60 and WISH cells from infection with vesicular stomatitis virus (VSV) [46] however, in this case RA significantly increased the ability of IFN-a to decrease virus replication. These apparently contrasting effects of RA on hCMV as compared to HSV-1 or VSV replication further illustrate the potential for retinoids to act either positively or negatively in host resistance to viral infection and anti-viral immunity. Retinoid-IFN interactions are further discussed later in this chapter. 

With the use of an indirect method for quantifying retinoids, namely a luciferase reporter gene construct containing two RA response elements (RAREs) from the RARp gene, Chen et al. confirmed significant RA activity in Xenopus embryos [46]. Later it was shown that the reporter construct used by Chen et al. can be activated by all-frans-RA, 9-cis-RA and synthetic ligands selective for RARs in Xenopus embryos [47]. 

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