Genetic Dissection of Glucocorticoid Receptor Function

Journal/Book: Z Rheumatol 1999; 58: 294. 1999;

Abstract: G Schütz; Molecular Biology of the Cell I German Cancer Research Center Heidelberg Glucocorticoids are involved in numerous physiological processes. Most of the effects are thought to be mediated by the glucocorticoid receptor (GR) via activation and repression of gene expression. Activation requires binding of a receptor dimer while repression is mediated in many cases by protein-protein interaction of GR monomers with other transcription factors. To analyse glucocorticoid receptor function in vivo several mutations were generated in the mouse. Mice with a disrupted GR gene (null mutation) die shortly after birth due to respiratory failure indicating an important role of GR in lung function. To separate activating from repressing functions of the GR a point mutation in the D-loop of the receptor which is required for receptor dimerization was generated with a Cre-loxP based strategy. Mice carrying this point mutation (GRdim) survive and allow to distinguish between GR functions dependent on DNA binding and those mediated by protein-protein interaction. Using cells from this mutant the molecular mechanism of cross-talk of GR with AP1 and NFkB was analyzed. Effects of glucocorticoids on AP1-controlled functions are not altered in GRdim mice suggesting that effects of GR on AP1 activity do not require DNA-binding. Further DNA-binding-independent activity of the receptor is sufficient for immunosuppression in vivo. Since mice with a disrupted GR gene die after birth cell-specific mutations have been generated with the Cre-loxP system. The GR gene was inactivated in liver thymus macrophages and brain respectively. Absence of GR in brain leads to alterations in control via the hypothalamic-pituitary-adrenal axis. The mutant mice appear to be less anxious revealing an involvement of GR in emotional behaviour and are impaired in learning and memory as shown in water maze studies. ... le

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