Retinoid receptors gene targeting

The concept of drug development is based on the findings that retinoid receptors (RARs and RXRs) offer a new approach by targeting different genes depending on the activated retinoid receptor complexes. The multiplicity of these retinoid signaling pathways affords potential for therapeutic opportunity as well as retinoid therapy associated undesired side effects. It is possible that the indiscriminate activation of all pathways by nonspecific retinoid ligands could lead to unacceptable side effects so that any enhanced efficacy would be obtained at the cost of enhanced toxicity. 

Vitamin A absorbs UV light between 300 and 350 nm. After acute exposure to UVA or UVB a dose-dependent decrease of vitamin A was shown in mouse59 and humans.84 UV irradiation markedly reduced mRNA and protein of the nuclear retinoid receptors RARy and RXRa in humans and led to a near loss of retinoic acid induction of the RAR/RXR target genes and the cellular retinoic acid binding protein II thus effectively causing additionally a functional vitamin A deficiency.85... 

J. Bastien, C. Rochette-Egly, Nuclear retinoid receptors and the transcription of retinoid-target genes, Gene 2004, 328,1-16. 

Gene targeting in embryonic stem (ES) cells is a powerful technique for the modification of the mouse genome (1-3). Regarding the retinoid receptors, a number of laboratories have reported the phenotype of mice in which a given retinoic acid receptor (RAR) or retinoid X receptor (RXR) has been inactivated by this technique (4-12). In addition, a number of cellular retmoid-binding protein-null mice have also been generated (13-15). 

Water-insoluble hormones (steroid, retinoid, and thyroid hormones) readily pass through the plasma membrane of their target cells to reach their receptor proteins in the nucleus (Fig. 23-4). With this class of hormones, the hormone-receptor complex itself carries the message it interacts with DNA to alter the expression of specific genes, changing the enzyme complement of the cell and thereby changing cellular metabolism (see Fig. 12 10). 

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