Retinoic Acid Receptors and Gene Regulation

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Vitamin A exerts its effects via retinoic acid and retinoid receptors, which are found in the nucleus of the cell. Retinol is converted to all-trans-retinoic acid and 9-cis retinoic acid in the cytoplasm. Retinoic acid influences gene activation through specific receptors which belong to the superfamily of thyroid and steroid receptors (231). Retinoic acid receptors (RARs) act as transcriptional activators for many specific target genes. The R AR is expressed as isoforms, referred to as RAR a, P, and y, and retinoid-x receptor (RXR) is also expressed as isoforms, referred to as RXR a, P, and y (232). All-trans retinoic acid is a ligand for RARs, whereas 9-cis retinoic acid is a ligand for both RARs and RXRs. 9-cis-retinoic acid is functionally distinct from all-trans-retinoic acid, and inter-conversion may exist between the two isomers. Each RAR and RXR has a specific DNA-binding domain by which these nuclear receptors may effect transcriptional activity.

The DNA sequences which interact with RAR and RXR are known as retinoic acid response elements (RAREs). RAR and RXR receptors form heterodimers, which bind to DNA and control gene expression. In addition, RXR receptors also can form heterodimers with the thyroid hormone receptor, vitamin D3 receptor, peroxisome proliferator-activated receptors, and a number of "orphan receptors." Most RAREs seem to occur in the regulatory region of genes. In the presence of 9-cis retinoic acid, RXR/RXR homodimers may form and recognize a subset of RAREs or inhibit the formation of certain heterodimers. Orphan receptors such as chicken ovalbumin up-stream promoter transcription factor (COUP-TF) (233), ARP-1, TAK1 (234), RVR (235), RZR (236), and thymus orphan receptor (TOR) (237) may repress or modulate the induction of genes by retinoic acid. The three-dimensional structures of several different DNA-binding complexes of RXR have been elucidated (238-240). RARs and RXRs may interact with multiple transcriptional mediators and/or corepressors, adding an enormous level of complexity to regulation of retinoic acid responses. Other vitamin A metabolites in the retroretinoid family may support biological functions via a pathway that is distinct from the retinoic acid pathway. 14-hydroxy-4,14-retro retinol supports whereas anhydroretinol inhibits cell growth (241,242). In addition, the oxoretinoids may play a role as RAR ligands (243).

Recently described nuclear receptor-associated proteins, such as SMRT/N-CoR, Sin3, and histone deacetylases (HDACs)-1 and -2 and histone acetylases (CBP/p300 and P/ CAF), appear to function as corepressors and coactivators of transcription. A binary paradigm has emerged as an attempt to explain how these proteins work. Unligated receptors bind to response elements of target genes and repress transcription through recruitment of a repressor complex containing corepressors, and transcription is repressed (244,245). Under these conditions, DNA is compact and packaged into chromatin. Ligand binding causes the dissociation of corepressor proteins and promotes the association of coactivators with liganded receptors. Coactivators associated with complexes displaying histone acetyltransferases (HAT), methultransferase, and kinase or ATP-dependent remodeling (SWI/SNF) activities lead to changes that reduces the compact nature of chromatin (245). The corepressors then dissoaciate, and a mediator complex known as the Srb and mediator protein-containing complex (SMCC) assembles. SMCC mediates the entry of the tran-scriptional machinery to the promoter, with resulting initiation of transcription (245).

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