Functional Analysis of the Glucocorticoid Receptor

Abstract

An increased knowledge of the mechanisms underlying signal transduction and regulation of gene expression is fundamental for our understanding of developmental biology, cell cycle regulation, endocrinology and carcinogenesis. In this context studies on the basic molecular biology and biochemistry of receptors and other transcription factors are of paramount interest. The steroid/thyroid hormone receptor superfamily of ligand inducible transcriptional activators includes receptors for steroid and thyroid hormones, vitamin D, retinoic acid, and a large group, still growing in number, of so called orphan receptors with unknown ligands and physiological functions (Evans, 1988; Beato, 1989; Carson-Jurica et al, 1990; Wahli and Martinez, 1991; Power et al 1992). The cloning and characterization of cDNAs encoding the various members of this superfamily has revealed a high level of molecular identity among the nuclear receptors. Common to all the nuclear receptors of this superfamily is their modular structural architecture (Fig. 1). They all harbor three major autonomous functional domains; an N-terminal domain with important functions for full transcriptional activity, a central DNA binding domain which shows the highest degree of structural homology among the members, and a C-terminal ligandbinding domain (Gustafsson et al., 1987; Carson-Jurica et al, 1990; Wahli and Martinez, 1991; Gronemeyer, 1992). These three domains have been further subdivided into six regions, A to F (Krust et al, 1986), that are more or less homologous between the various members: A/B, F, modulating regions; C, DNA binding region; D, ”hinge” region: E, ligand binding region (Fig. 1).