DNA-Dependent Cofactor Selectivity of the Glucocorticoid Receptor

Abstract

The glucocorticoid receptor (GR) is one of the best-characterized steroid receptors and essential for the regulation of multiple physiological processes. Due to their multiple inhibitory effects on the immune system, glucocorticoids are especially suited for treatment of inflammations and autoimmune diseases, but prolonged therapy results in severe metabolic side effects due to alterations in glucose and lipid metabolism. Further side effects include osteoporosis, atrophy of the skin, myopathy, and psychosis. In the absence of its ligand, the GR is localized in the cytoplasm as part of a multiprotein complex composed of GR, heat-shock proteins, and immunophilins. Binding of glucocorticoids to the receptor induces release of GR from this complex and subsequent translocation to the nucleus. This leads to binding of receptor dimers to specific DNA motifs in the regulatory regions of target genes and to activation of their transcription (Beato et al. 1995; Mangelsdorf et al. 1995). The function of dimeric receptors is also influenced considerably by neighboring transcription factors (Leers et al. 1994; Burcin et al. 1997). The GR shows further types of action, which do not require the binding of receptor dimers to DNA-recognition sequences (Heck et al. 1994; Reichardt et al. 1998). Binding of the ligand to the receptor leads in most of these cases to repressed activity of genes which are activated through other transcription factors, for example during the immunogenic reaction. This transcriptional crosstalk with transcription factors like AP-1, NF-κB or Stat5 occurs without direct binding to DNA; presumably on the basis of protein-protein interactions with the DNA-bound transcription factors (Jonat et al. 1990; Lucibello et al. 1990; Yang-Yen et al. 1990; Schüle and Evans 1991; König et al. 1992; Stöcklin et al. 1996; Heck et al. 1997). In another crosstalk mechanism (the proliferin gene), the GR presumably binds as a monomer along with other transcription factors to a “half” recognition sequence in a “composite element” (Diamond et al. 1990). Furthermore, negative response elements (nGREs; nTREs) have been described for glucocorticoid and also thyroid hormone receptors (Drouin et al. 1993; Saatcioglu et al. 1994; Lefstin and Yamamoto 1998; Awad et al. 1999). The molecular mechanism of all of these forms of gene repression via GR remains unclear.