Increasing the Complexity of Coactivation in Nuclear Receptor Signaling

• Published in: Cell 1999-04, Vol.97 (1), p.5-8
• Main Author: Freedman, Leonard P
• Format: Article
• Language: English
• Subjects: Animals; Humans; Phosphorylation; Receptors, Cytoplasmic and Nuclear - metabolism; Receptors, Cytoplasmic and Nuclear - physiology; Signal Transduction - physiology
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/S0092-8674(00)80708-4

Nuclear receptors lead somewhat of a double life. In many respects, these proteins are indistinguishable from other eukaryotic factors that regulate transcription. Nuclear receptors bind selectively to DNA, primarily as dimers through two characteristic zinc finger modules and a dimerization region that directs self-interaction or hetero-partnering. Moreover, they possess identifiable activation functions (AFs) that confer transactivation potential to heterologous DNA-binding domains. However, an important feature of nuclear receptors that distinguishes them from other transcription factors is that these proteins possess a hair-trigger switch, which is conferred by their ligand-binding domain (LBD). It is here that the receptors have evolved their uncanny ability to stifle intrinsic transactivation potentials when not bound by their cognate ligands and to immediately induce them when a given ligand makes a stereospecific, high-affinity interaction with a pocket in the LBD waiting to accomodate it. The ligands for nuclear receptors include steroids, retinoids, vitamin D, thyroid hormone, prostanoids, and farnesoids. Their combined effects are vast, influencing virtually every fundamental biological process, from development and homeostasis, to proliferation and differentiation. As more ligands have been uncovered for orphan receptors, it is becoming increasingly apparent that nonendocrine pathways, including those involving protein kinases and metabolic products, are also responsible for signaling. Because this family of receptors are intracellular, they are direct mediators of the action of their cognate hormone. Although some steroid receptors are compartmentalized initially to the cytoplasm as complexes with heat shock proteins acting as chaperones and subsequently translocate to the nucleus as a consequence of ligand binding, most receptors are prelocalized to the nucleus. How then do the ligands exert their inducing effects on nuclear receptor activity if they already reside in the nucleus (presumably DNA-bound), and how do some receptors become activated by kinase cascades independently of their cognate ligands? The answer appears to be reflected in another aspect of the double life of nuclear receptors: an initial association with transcriptional corepressors and subsequent ability to recruit coactivators in response to ligands and other signals. A rapidly expanding repertoire of coactivators, including a novel RNA-based one reported in this issue of