Molecular Mechanism Of Action Of Ra

RA functions by binding to ligand-inducible transcription factors (nuclear receptor proteins belonging to the steroid/thyroid hormone receptor super-family) that activate or repress the transcription of downstream target genes (for review see Chambon, 1996; Soprano and Soprano, 2003). Six nuclear receptors (termed RARa, RARb, RARg, RXRa, RXRb, and RXRg), encoded by distinct genes, have been demonstrated to mediate the actions of RA. The natural metabolites all-trans RA (atRA) and 9-cis RA are high-affinity ligands for RARs, whereas 9-cis RA, phytanic acid, docosahexanoic acid, and unsaturated fatty acids, have been suggested to bind RXRs.

These proteins, as heterodimers (RAR/RXR) or homodimers (RXR/RXR), function to regulate transcription by binding to DNA sequences located within the promoter of target genes called retinoic acid response elements (RARE) or retinoid X response elements (RXRE), respectively (Fig. 1). RAREs consist of direct repeats of the consensus half-site sequence AGGTCA separated most commonly by five nucleotides (DR-5) while RXREs are typically direct repeats of AGGTCA with one nucleotide spacing (DR-1). The RAR/ RXR heterodimer binds to the RARE with RXR occupying the 5' upstream half-site and RAR occupying the 3' downstream half-site.

FIGURE 1. Mechanism of RA-induced gene transcription. In the inactivate promoter, the RAR and RXR exist as a heterodimer bound through its DNA-binding domain (DBD) to the RARE DR-5. Corepressors bind to RAR and recruit HDAC causing transcriptional repression. When RA is added, transcription is activated by RA binding to the RAR. The RAR bound to RA then recruits coactivators and HAT.

FIGURE 1. Mechanism of RA-induced gene transcription. In the inactivate promoter, the RAR and RXR exist as a heterodimer bound through its DNA-binding domain (DBD) to the RARE DR-5. Corepressors bind to RAR and recruit HDAC causing transcriptional repression. When RA is added, transcription is activated by RA binding to the RAR. The RAR bound to RA then recruits coactivators and HAT.

Over the last several years, a large number of proteins that interact with RARs have been demonstrated to play an important role in the ultimate control of their transcriptional activity (for review see Hart, 2002; Jepsen and Rosenfeld, 2002; Wei, 2003; Westin et at., 2000). In the absence of RA, the apo-receptor pair (RAR/RXR) binds to the RARE in the promoter of target genes and RAR recruits corepressors. These corepressors mediate their negative transcriptional effects by recruiting histone deacetylase complexes (HDACs). HDACs remove acetyl groups from histone proteins inducing a change in the chromatin structure causing DNA to be inaccessible to the transcriptional machinery. On the other hand, on RA binding (at physiological levels), there is a conformational change in the structure of the ligand-binding domain that results in the release of the corepressor and the recruitment of coactivators to the AF-2 region of the receptor. Some coactivators interact directly with the basal transcription machinery to enhance transcriptional activation, while others exhibit histone acetyltransferase (HAT) activity. HAT

acetylates histone proteins causing the activation of transcription of the associated gene.

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