The RXR heterodimers and orphan receptors

DJ Mangelsdorf, RM Evans - Cell, 1995 - Elsevier
DJ Mangelsdorf, RM Evans
Cell, 1995Elsevier
The nuclear receptor superfamily is comprised of over 150 different proteins that have
evolved to mediate a complex array of extracellular signals into transcriptional responses.
Many, but not all, of these proteins directly bind to signaling molecules, which, because of
their small lipophilic character, can easily enter the target cell. Thus, unlike membrane-
bound receptors, the nuclear receptors are intracellular and function to control the activity of
target genes directly. In aggregate, these target genes comprise a genetic network whose …
The nuclear receptor superfamily is comprised of over 150 different proteins that have evolved to mediate a complex array of extracellular signals into transcriptional responses. Many, but not all, of these proteins directly bind to signaling molecules, which, because of their small lipophilic character, can easily enter the target cell. Thus, unlike membrane-bound receptors, the nuclear receptors are intracellular and function to control the activity of target genes directly. In aggregate, these target genes comprise a genetic network whose coordinate activity defines the physiologic response. The purpose of this review is to establish the historical links between the steroid and nonsteroid receptor signaling systems, to chart the explosive development of the retinoid X receptor (RXR) heterodimer and orphan receptor family, to explain the impact of these discoveries on our understanding of the mechanisms of hormonal signaling, and, finally, to present emerging issues and implications of these studies for animal development, physiology, and human disease.
Mechanism of Action Although the principle mechanism of action of heterodimerit and orphan receptors is similar to that for the steroid hormone receptors, there are several important differences. In contrast with the steroid receptors, the ligands for this family are chemically diverse, including vitamin D, thyroid hormone, retinoids, and prostanoids. Furthermore, not all of these ligands are exclusively endocrine, and they may be activated by metabolic pathways within the target cells (Figure 1). Others may be entirely produced in the target cell and thus have no true hormonal feature. In addition, as will be discussed below, not all members of this family can be expected to be hormone responsive, suggesting that alternative ligand-independent pathways for activation exist. Phosphorylation is one potential candidate for mediating receptor function by such a pathway (reviewed by Weigel, 1994). Another mechanism bywhich receptors can modulate gene expression is by crosscoupling to augment or inhibit signaling pathways mediated by other classes of transcription factors. Perhaps the best example is the inhibition of AP-1 (JunlFos) action by glucocorticoids, retinoids, and thyroid hormones (Pfahl, 1993; reviewed by Beato et al., 1995 [this issue of Cc//l). While the molecular basis of these inhibitory effects are poorly understood, they allow hormones to regulate genes without requiring the receptors to bind to DNA. DNA-Binding Motifs
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