Activation of Retinoic Acid Receptor-dependent Transcription by All-trans-retinoic Acid Metabolites and Isomers

Abstract

. By comparing the -fold induction of luciferase activity, all retinoids tested were equipotent at transactivating RARE-tk-Luc whatever the RAR considered. However, the best induction of the transcription was obtained for RAR␣, which was 5-fold higher than for RAR␤ and 10-fold higher than for RAR␥. In conclusion, these data show that ATRA metabolites can bind to and activate the three RARs with variable relative affinity but with similar efficacy. These results suggest that ATRA metabolites may activate several signaling pathways and probably play an important role in cellular physiology and cancer therapy.Vitamin A and its derivatives (retinoids) are natural compounds that play central roles in several physiological processes such as embryonic development, proliferation, differentiation, and apoptosis (reviewed in Ref. 1). Beside their role in the physiology of normal cells, retinoids possess pharmacological properties used in dermatology and in cancer therapy, including epithelial cancers, precancerous lesions (2), and acute promyelocytic leukemia (3).All-trans-retinoic acid (ATRA 1 ) (see Fig. 1), which is considered as one of the most active retinoid, is metabolized by several cytochrome P450s (CYPs) (4). CYPs are heme proteins catalyzing the oxidation of several endobiotics and xenobiotics such as environmental pollutants and drugs. The CYP-mediated metabolism may transform some substrates into inactive compounds but can also lead to the formation of biologically active metabolites. ATRA is metabolized into several oxidized metabolites, including 4-oxo-RA, 4-OH-RA, 18-OH-RA, and 5,6-epoxy-RA (Fig. 1) (reviewed in Ref. 5). All of these metabolites have shown biological activity, e.g. 4-oxo-RA is a highly active modulator in embryogenesis (6). It has also been shown that 4-oxo-RA, 4-OH-RA, and 5,6-epoxy-RA can inhibit the growth of several breast cancer cell lines (7,8). Some of these metabolites can inhibit growth and induce differentiation of rhabdomyosarcoma cells (9) and regulate the expression of several genes involved in differentiation and embryogenesis (6, 10). We have recently shown that ATRA metabolites, including 4-oxo-, 4-OH-, 18-OH-, and 5,6-epoxy-RA, can induce granulocytic differentiation of NB4 acute promyelocytic leukemia cells, elicit nuclear bodies reorganization, and induce the degradation of the chimeric protein PML-RAR␣ (11).The retinoid signal is transduced by two families of nuclear receptors, the retinoic acid receptor (RAR) family comprising three isotypes, RAR␣, RAR␤, and RAR␥, and the retinoid X receptor (RXR) family comprising also three isotypes, RXR␣, RXR␤, and RXR␥ (12). Each RAR and RXR isotype includes several isoforms. These receptors belong to the superfamily of nuclear hormone receptors and act as ligand-activated transcription factors (reviewed in Refs. 12 and 13). RARs function as a heterodimer together with RXR. The ligand-receptor complexes act as inducible transcription regulators of several genes by binding to specific retinoic acid response elements (RARE). Two type...

Cyp26 enzymes generate the retinoic acid response pattern necessary for hindbrain development

“…This demonstrates that, as for other phenotypes observed in cyp26a1-mutant fish and mice (Emoto et al, 2005;Niederreither et al, 2002), the posteriorized hindbrain phenotype caused by blocking all Cyp26 activity is due to the accumulation of excess RA and not to the absence of bioactive Cyp26-generated RA derivatives. Although such derivatives have been observed to have significant retinoidal effects in cells and in embryos, and have been postulated to have functions in vivo (Idres et al, 2002;Pijnappel et al, 1993), we see no evidence for their having a role in hindbrain patterning.…”

The neurobiology of retinoic acid in affective disorders

“…RA then enters the nucleus and binds to the RA receptors to activate gene transcription. Other retinoids are also known to bind to the RA receptors, including 4-oxo-retinoic acid and other oxidative derivatives (Idres et al 2002), 4-oxo-retinol (Ross and De Luca 1996) and didehydroretinol (Sani et al 1997). At the present time, however, RA is the only retinoid detected in the adult brain that activates the RAR class of receptors (Kane et al 2005).…”

The cleavage product ΔPML–RARα contributes to all-trans retinoic acid-mediated differentiation in acute promyelocytic leukemia cells

“…We and other groups have found that ATRA and As 2 O 3 proteolized PML-RARa differently (Jing et al, 2001;Zhu et al, 2001). Thus, ATRA, unlike As 2 O 3 , leads to a decrease in full-length PML-RARa with formation of a specific 85 kDa fragment product, termed DPML-RARa in NB4 cells (Figure 2a) Gianni et al, 1998;Fanelli et al, 1999;Idres et al, 2001;Jing et al, 2001;Jing et al, 2002). DPML-RARa appears to delete the N-terminal portion of PML, since the RARa antibody used is against the C-terminal RARa region.…”