Retinoids (vitamin A and its metabolites) are suspected of regulating diverse aspects of growth, differentiation, and patterning during embryogenesis, but many questions remain about the identities and functions of the endogenous active retinoids involved. The pleiotropic effects of retinoids may be explained by the existence of complex signal transduction pathways involving diverse nuclear receptors of the retinoic acid receptor (RAR) and retinoid X receptor (RXR) families, and at least two types of cellular retinoic acid binding proteins (CRABP-I and -II). The different RARs, RXRs, and CRABPs have different expression patterns during vertebrate embryogenesis, suggesting that they each have particular functions. Another level at which fine tuning of retinoid action could occur is the metabolism of vitamin A to active metabolites, which may include all-trans-retinoic acid, all-trans-3,4-didehydroretinoic acid, 9-cis-retinoic acid, and 14-hydroxy-4,14-retroretinol. Formation of the metabolite all-trans-4-oxo-retinoic acid from retinoic acid was considered to be an inactivation pathway during growth and differentiation. We report here that, in contrast, 4-oxo-retinoic acid is a highly active metabolite which can modulate positional specification in early embryos. We also show that this retinoid binds avidly to and activates RAR beta, and that it is available in early embryos. The different activities of 4-oxo-retinoic acid and retinoic acid in modulating positional specification on the one hand, and growth and differentiation on the other, interest us in the possibility that specific retinoid ligands regulate different physiological processes in vivo.
There are many indications that active retinoids are regulatory signals during vertebrate embryogenesis. Treating vertebrate embryos with retinoids can cause teratogenic defects, including specific derangements of the main body axis. Other data show that early vertebrate embryos contain physiologically relevant concentrations of active retinoids and express retinoid binding proteins and receptors; that knockouts of retinoid receptors can induce homeotic defects; and that relevant developmental control genes are regulated by retinoid response elements. Here, we discuss the possibility that retinoids are developmental signals which regulate axial patterning in the early vertebrate embryo.
Previous studies have shown that all-trans-retinoic acid (RA) inhibits in vitro proliferation of hormone-dependent human breast cancer cells but not the growth of hormone-independent cells. Here we report on RA metabolism in breast cancer cells as examined by high performance liquid chromatography analysis and found a correlation with sensitivity to growth inhibition by RA. RA-sensitive T-47D and MCF-7 cells exhibited high rate metabolism to polar metabolites, whereas RA-resistant MDA-MB-231 and MDA-MB-468 cells metabolized RA to a much lesser extent, and almost no polar metabolites could be detected. The high metabolic rate in RAsensitive cells appears to be the result of autoinduction of RA metabolism, whereas RA-resistant cells showed no such induction of metabolism. We observed furthermore that transfection with retinoic acid receptor-␣ expression vectors in RA-resistant MDA-MB-231 cells resulted in increased RA metabolism and inhibition of cell proliferation. Metabolism of RA, however, seems not to be required to confer growth inhibition of human breast cancer cells. The biological activity of the polar metabolites formed in RA-sensitive cells was found to be equal or lower than that of RA, indicating that RA itself is the most active retinoid in these cells. Together our data suggest that RA-sensitive cells contain mechanisms to activate strongly the catabolism of RA probably to protect them from the continuous exposure to this active retinoid.Retinoids are a group of naturally occurring (e.g. all-transretinoic acid; RA 1 ) and synthetic analogs of vitamin A which play an important role in cellular growth and differentiation (1, 2). The actions of retinoids are mediated by two types of receptors, the retinoic acid receptors (RARs) and retinoid X receptors (RXRs) (3, 4). Both receptor types belong to the steroid-thyroid hormone receptor superfamily and regulate transcription in the presence of their ligands. RARs can be activated both by RA and 9-cis-RA, whereas only 9-cis-RA binds to RXRs (5, 6).Retinoids are highly effective in preventing chemically induced carcinogenesis in experimental animals (7) and can inhibit proliferation of a large variety of normal and neoplastic cell types in vitro (8). More recently the effectiveness of retinoids in the treatment and prevention of a number of human cancers has been established (9 -15).Unfortunately, lack of response to retinoid treatment and relapse of tumors are commonly observed. It is becoming increasingly clear that variations in metabolic rates of retinoids may be involved in the differences in retinoid response. Interindividual variation in the pharmacokinetics of retinoids has been reported for several malignancies, and a recent study suggested that high rate metabolism of RA is linked to an increased risk of squamous or large cell lung cancer (16 -18). In acute promyelocytic leukemia patients, relapse and resistance to RA have been associated with a rapid and marked decrease of retinoid levels in the plasma (19,20).Retinoid resistance has also been docu...
We report identification of 9-cis-4-oxo-retinoic acid (9-cis-4-oxo-RA) as an in vivo retinoid metabolite in Xenopus embryos. 9-Cis-4-oxo-RA bound receptors (RARs) ␣, , and ␥ as well as retinoid X receptors (RXRs) ␣, , and ␥ in vitro. However, this retinoid displayed differential RXR activation depending on the response pathway used. Although it failed to activate RXRs in RXR homodimers, it activated RXRs and RARs synergistically in RAR-RXR heterodimers. 9-Cis-4-oxo-RA thus acted as a dimer-specific agonist. Considering that RAR-RXR heterodimers are major functional units involved in transducing retinoid signals during embryogenesis and that 9-cis-4-oxo-RA displayed high potency for modulating axial pattern formation in Xenopus, metabolism to 9-cis-4-oxo-RA may provide a mechanism to target retinoid action to this and other RAR-RXR heterodimer-mediated processes.Much evidence implicates retinoids (vitamin A and metabolites) in regulating embryonic pattern formation as well as growth, differentiation, reproduction, metabolism, and homeostasis (1-4). Many important effects of retinoids are mediated by two families of nuclear receptors: retinoic acid (RA) receptors (RARs) and retinoid X receptor (RXRs), each consisting of three types (␣, , and ␥), there being several isoforms of each type (5-7). RARs and RXRs are retinoid ligand-dependent transcription factors, which can act via specific DNA response elements consisting of direct repeats of the hexameric motif RG(G͞ T)TCA. Two main retinoid response pathways are known. RARs and RXRs heterodimerize and then activate transcription via RA response elements consisting of direct repeats (DRs) spaced by 2 (DR-2) or 5 (DR-5) base pairs. Both the RAR and RXR partners of the heterodimer can be ligand activated in vivo, resulting in synergistic activation (8-13). RXRs also homodimerize, and this homodimerization contrasts with RAR-RXR heterodimerization in being ligand stimulated (14-17). RXR homodimers activate transcription from retinoid X response elements (RXREs) consisting of DRs spaced by 1 (DR-1) base pair. In addition to these two main pathways, retinoid receptors interact with other signaling pathways, either via heterodimerization between RXR and other nuclear hormone receptors or via crosstalk with AP-1.Paralleling the multiplicity of retinoid receptors, several natural retinoids are known to act as retinoid receptor ligands (4, 18-23). These fall into two groups. Ligands that activate RARs only include all-trans-RA, all-trans-3,4-didehydroretinoic acid (ddRA), all-trans-4-oxo-retinoic acid (4-oxo-RA), all-trans-4-oxoretinal, and all-trans-4-oxo-retinol. These ligands activate only RAR-RXR heterodimers and act via the RAR part of the heterodimer. The second group, including 9-cis-RA and 9-cis-3,4-didehydroretinoic acid, activates both RARs and RXRs. 9-Cis-RA has been shown to activate RAR-RXR heterodimers more efficiently than natural RAR ligands, suggesting that both partners of the heterodimer are activated by this ligand (8, 12). 9-Cis-RA also activat...
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