Retinoids action

Agarwal C, Chandraratna RA, Johnson AT, Rorke EA, and Eckert RL [1996] AGN193109 is a highly effective antagonist of retinoid action in human ectocervical epithelial cells. J Biol Chem 271 12209-12212... 

Retinoid action depends on binding to both cytosolic and nuclear retinoic acid receptors (RARs). RARs have distinct DNA and retinoid-binding domains, and they function as pairs and bind to the retinoic acid receptor element (RARE) to regulate transcriptional activity. 

Nau, H. and W.S. Blaner Retinoids The Biochemical and Molecular Basis erf Vitamin A and Retinoid Action, bl. 139, Springer-Verlag, Inc.. New York, NY,... 

Vogel S, Gamble MV, Blaner WS Retinoid uptake, metabolism and transport, in Nau H, BlanerWS (eds) The Handbook of Experimental Pharmacology, Retinoids The Biochemical and Molecular Basis of Vitamin A and Retinoid Action. Springer-Verlag, Heidelberg, 1999, pp. 31-96. 

Noy N (2000) Retinoid-binding proteins mediators of retinoid action. BiochemicalJour-nfl/348(Pt 3), 481-95. 

Noy, N. 2000. Retinoid-Binding Proteins Mediators of Retinoid Action. Biochem J 348 481-95. 

The specificity of the test system used is of critical importance. It is essential that positive responses be limited to chemical structures that are primary effectors of retinoid action. The highly specific nature of the structural requirements for biological activity is discussed in the next section however, it is clear that a useful retinoid assay should not give a sensitive response to chemical structures that have only minimal resemblance to retinol and retinoic acid, such... 

Nuclear-retinoid receptors provide a mechanism of retinoid action, but most likely where expressed, the cytosolic cellular retinoic acid-binding proteins (CRABPs) also affect the ability of retinoids to initiate biological signals (1,2). holo-CBlABP I sequesters retinoic acid (RA) with a value that may be <1 nM, and serves as a high-affinity 2 nM), efficient substrate of RA... 

D. Cell Cycle-Specific Locus of Retinoid Action. 233... 

In this section we first discuss the effects of retinoids on nonneoplastic cells in culture and then the effects of retinoids on cultured neoplastic cells. As discussed earlier, the cell types affected are not limited to epithelial cells but include also cells of mesenchymal origin and cells derived from neural ectoderm. Since most of these cell culture systems require serum, they inherently include retinoids. However, it is not known whether all of these cell types have a requirement for retinoids. Therefore, one should always attempt to relate studies of retinoid action in vitro to the function of those particular cell types in vivo. 

Whether the cells are derived from an established cell line or from primary cultures is another element that must be considered. While primary cultures most closely resemble the parent cell type in vivo, most cell culture experiments have been carried out using established cell lines, many of which are aneuploid. The ready availability of these established cell lines, many of which are neoplastic, and their reproducible response pattern have made them the subject of numerous investigations of retinoid action. However, their physiological relevance may be questionable therefore it is important, whenever possible, to relate the observed in vitro effects to similar effects of retinoids in vivo. 

It is clear that much more information is needed regarding the primary cellular targets of retinoid action before the basis of these diverse results can be analyzed. 

Thus, although the details must be worked out more thoroughly, the framework exists for the participation of the intracellular retinoid-binding proteins CRBP and CRABP in a steroid hormone-like mechanism of control of gene expression. The question that must be asked is whether these binding proteins can be shown to be necessary for retinoid action (see also Chapter 9). In experiments with cultured cells, there is evidence both for and against this theory. In... 

Hie molecular hypothesis of retinoid action that is compatible with the broadest range of experimental data on retinoid control of cell growth, differentiation, and transformation is to suggest that retinoids modify genomic expression. This, of course is not a new idea. Almost IS years have passed since it was first demonstrated that retinoids might be controlling RNA synthesis (Zachman, 1%7 Johnson et al., 1969 Zile and DeLuca, 1970) however, these early studies were subject to criticism of experimental design. Thus, it is only lately that we have been able to address experimentally the questions of (1) which... 

Retinoids and the Immune System Immunostimuiation by Vitamin A 385 C. Mechanism of Retinoid Action... 

The toxicology, teratogenic profile and mechanism of retinoid action have been reviewed [1, 11, 18-20]. Among the drawbacks to currently approved retinoids, 13-cw-retinoic acid... 

Zelent A (1995) Molecular mechanisms of retinoid action. In L Degos, DR Parkinson (eds) Retinoids in Oncology. Springer-Verlag, Heidelberg, 3-25... 

Pharmacology and molecular mechanisms of retinoid action in skin... 

The discovery of retinoic acid receptors in the late 1980 s was pivotal for our understanding of the mechanisms of retinoid action, because it was the first demonstration of the existence of a retinoid-responsive transcription factor. Both retinoic acid receptors (RARs) and retinoid X receptors (RXRs) have three different family members, a, P, and y, each encoded by different genes. KW-trans retinoic acid (/-RA) and its stereoisomer 9-cis retinoic acid (9c-RA), bind to RARs with similar high affinity [16]. The off-rates for t-RA binding to RAR-a, RAR-p, and RAR-y are similar [17]. However, for 9c-RA, the off-rates differ it is fastest with RAR-y and slowest with RAR p. Because of these differences, RARs tend to prefer t-RA when they are in the presence of mixtures of t-RA and 9c-RA. This is especially true for RAR-y, which demonstrates a strong preference for t-RA. t-RA does not bind to RXRs, only 9c-RA does [18, 19]. 

Umemiya H, Fukasawa H, Ebisawa M, Eyrolles L, Kawachi E, Eisenmann G, Gronemeyer H, Hashimoto Y, Shudo K, Kagechika H (1997) Regulation of retinoidal actions by diazepinylbenzoic acids. Retinoid syner... 

Finally, when we evaluate ER cells, RA and 13-cw retinoic acid (13cRA) seem to be generally less effective, except when used at very high concentrations, than in ER cells, both in terms of proliferation inhibition and apoptosis induction, and modulation of cellular differentiation fails to occur under any experimental condition (see also Figs. 1 and 2). Probably one or more alterations in the complex pathway of retinoid action occurs in these cells, and these anomalies make it difficult for the retinoids to exert their effects (e.g. low levels of RARa, low levels or altered forms of RARp). 

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