42 Retinoid Receptors as Transcription Factors

OVERVIEW The process by which retinoic acid (RA) and its congeners elicit their effects on vertebrate development and physiology is mediated by ligand-activated transcription factors that are members of the nuclear receptor superfamily. Thus far, two distinct classes of retinoid receptor genes have been detected, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs); each subclass contains three separate genes. An analysis of RAR and RXR ligand specificity, target gene specificity, and patterns of expression suggests that each receptor pathway has both overlapping and unique functions. The ability of the retinoid receptors to interact with other nuclear receptors as well as other classes of transcription factors further increases the diversity and complexity of retinoic acid responses. INTRODUCTION In 1913, a nutritive factor was discovered as a lipid component of butter, egg yolk, and cod liver oil that in vertebrate animals was found to be essential for growth (McCollum and Davis 1913; Osborne and Mendel 1913). The factor was subsequently isolated and called vitamin A. Today, vitamin A and its natural and synthetic derivatives (the retinoids) are known to play essential roles in vision, reproduction, epithelial differentiation, hematopoiesis, bone development, and pattern formation during embryogenesis (Sporn et al. 1984). There is also considerable evidence to suggest that retinoids have potent antiproliferative effects and may be effective in the treatment of a variety of human diseases, including cancer (Ong and Chytil 1983; Sporn et al. 1984). Although vitamin A participates in many diverse and apparently unrelated functions, it is known...