The Human Glucocorticoid Receptor: Molecular Mechanisms Controlling the Termination of Glucocorticoid Responses

J. A. Cidlowski, C. M. Jewell, B. Necela, A. Wallace, M. J. M. Schaaf, D. D. Dong

Molecular Endocrinology Group, Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, NIH, Research Triangle Park North Carolina, U.S.A.

Glucocorticoids are a vital class of steroid hormones that regulate a diverse array of physiological actions in all vertebrates. The actions of glucocorticoids are mediated via the glucocorticoid receptor, a product of a single receptor gene. However, recent studies have shown that multiple receptor isoforms can be generated from this gene via alternative splicing and alternative translation initiation mechanisms. These isoforms, along with post translational modification of the receptor (i. e. phosphorylation, ubiquitination), may contribute to the diverse and tissue specific responses to glucocorticoids. Therapeutically both natural and synthetic glucocorticoids are widely used to control a variety of inflammatory diseases including asthma, inflammatory bowel disease, dermatitis and arthritis. The effectiveness of these drugs is often compromised by premature termination of steroid responsiveness and the development of resistance to glucocorticoids. In the lecture I will present new molecular data on three aspects of glucocorticoid resistance and the termination of GR signaling: 1) the role of NF-κB in repression of GR signaling; 2) the role of post translational modification of glucocorticoid receptors in targeting the receptor for degradation in the proteasome; and 3) the molecular mechanism of hGRβ as a dominant negative receptor and the development of steroid resistance.