Crabp

Isomerasesl 9-cis RA

I RoDH

I RoDH

Retinal

Retinoid responses

FIGURE 2. The metabolic pathway and the cellular mechanism of RA action. The metabolic pathway of RA. Retinol is taken up from the blood, where it binds to retinol-binding proteins (RBPs) and rebinds intracellularly to cellular retinol-binding proteins (CRBPs). Intracellularly, retinol is converted to retinal by the retinol or alcohol dehydrogenases (RoDH), and retinal is further metabolized to RA by RALDHs. RA is bound in the cytoplasm by cellular RA-binding protein (CRABP). Alternatively, RA and its 9-cis isomer enter the nucleus and bind to RARs or RXRs, respectively. On dimerization of these receptors, RAR/RXR heterodimer or RXR/RXR homodimer, the activated receptors bind to a sequence of DNA known as the RA-response element (RARE). This latter action either activates or represses transcription of the target gene.

Retinoid responses

FIGURE 2. The metabolic pathway and the cellular mechanism of RA action. The metabolic pathway of RA. Retinol is taken up from the blood, where it binds to retinol-binding proteins (RBPs) and rebinds intracellularly to cellular retinol-binding proteins (CRBPs). Intracellularly, retinol is converted to retinal by the retinol or alcohol dehydrogenases (RoDH), and retinal is further metabolized to RA by RALDHs. RA is bound in the cytoplasm by cellular RA-binding protein (CRABP). Alternatively, RA and its 9-cis isomer enter the nucleus and bind to RARs or RXRs, respectively. On dimerization of these receptors, RAR/RXR heterodimer or RXR/RXR homodimer, the activated receptors bind to a sequence of DNA known as the RA-response element (RARE). This latter action either activates or represses transcription of the target gene.

Mangelsdorf et al., 1995; Petkovich, 1992). Retinoid receptors were cloned in the late 1980s and early 1990s (Benbrook et al., 1988; Brand et al., 1988; Hamada et al., 1989; Leid et al., 1992; Mangelsdorf et al., 1992; Ragsdale et al., 1989). RARs are activated by all-trans RA and its 9-cis isomer, while RXRs are only activated by 9-cis RA. These receptors act as ligand-dependent transcription factors. The RARs and RXRs function as hetero-dimers (Kastner et al., 1997b; Mangelsdorf and Evans, 1995). RAR-RXR heterodimers bind to specific genomic DNA sequences designated as RAREs, which are characterized by two half sites with the consensus sequence AGGTCA. These are generally arranged as direct repeats (DR) separated by two or five nucleotides. These heterodimers have two distinct functions: first, they modulate the frequency of transcription initiation of target genes after binding to RAREs in the promoters; and second, they affect the efficiency of other signaling pathways (cross talk) by unknown mechanisms. This cross talk suggests that retinoid receptors are also targets of other pathways (Chen et al., 1995; Zechel et al., 1994). Retinoids do not act solely through the two subunits of the RAR-RXR heterodimer. RXR is a promiscuous heterodimerization partner for various nuclear receptors such as the thyroid hormone receptors, vitamin D receptors, peroxisomal proliferator-activated receptor, and several other orphan receptors (Kliewer et al., 1992a,b; Schrader et al., 1993). Therefore, RXR ligands have the potential to affect the signaling of many pathways. The functions of RARs and RXRs are not limited to a direct transactivation process, as they also include transrepressive activity. Transcriptional interference may result when the receptor, bound to ligand, prevents other transcription factors, such as AP-1, from interacting with the transcription initiation complex (Yang-Yen et al., 1991; Zhou et al., 1999). This transrepressive function is likely responsible for a large part of the biological effects of retinoids. The nongenomic effects of RA have been demonstrated in recent studies. RA acts by promoting the activation of cytoplasmic-signaling cascades that control the activity of specific genes. It has been shown that in acute promyelocytic leukemia cells, the RA-induced differentiation process is associated with a rapid increase in the level of intracellular cAMP as well as protein kinase A activity. In contrast, no such change was observed in RA-resistant cells (Zhao et al., 2004). In SH-SY5Y neuroblastoma cells and NIH3T3 cells, RA treatment induces increased phosphoinositide 3-kinase (PI3K) activity and a rapid increase in phosphorylation of AKT in Ser-473 and extracellular-regulated kinase (ERK). RA-induced differentiation was impaired by inhibition of PI3K, indicating that RA, by activating the PI3K/AKT-signaling pathway, has an important role in the regulation of neuronal cell survival (Antonyak et al., 2002; Lopez-Carballo et al., 2002). In this respect, RA behaved much like estrogens, which have been reported to induce rapid activation of signaling pathways, such as ERK and AKT (Christ et al., 1999; Gerdes et al., 2000). With many interactions and numerous effects in target cells, these findings suggest that RA is a critical regulator of embryonic development and cellular and tissue homeostasis.

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