of Work: The glucocorticoid hormone action group studies how environmental stressors elicit and transmit metabolic signals. Our primary interest is in steroid receptor signalling, adaptation to chronic environmental stress as well as the development of resistance to glucocorticoids. Recent studies in our lab have shown that a mutual antagonism exists between pro-inflammatory cytokines and glucocorticoids. Specifically signal transduction by the glucocorticoid receptor is impaired in cells with active nuclear NfKB, and signal transduction by NfKB is impaired in cells with active nuclear glucocorticoid receptor. We are studying the mechanism of this antagonism and evaluating if NfKB is a generalized endocrine disruption. A second area of effort is aimed at understanding what role phosphorylation has in glucocorticoid receptor signal transduction. Glucocorticoid receptors are phosphoproteins, but there is currently little information on how phosphorylation affects receptor function. The function of phosphomutant receptors in terms of transcriptional activation and repression is being evaluated. Another focus of our work is on glucocorticoid receptor down regulation which leads to resistance to steroids. We have shown that the glucocorticoid receptor represses the expression of its own gene. This repression occurs via a consequence of the direct interaction of the glucocorticoid receptor with two intragenic binding sites within the gene. These sites have been mapped, functionally evaluated, and mutant receptors are being studied. We have recently described the widespread expression of a second form of human glucocorticoid receptor. This receptor, termed hGRBeta, is an alternatively spliced product from the same gene and functions as a strong dominant negative inhibitor of glucocorticoid receptor signalling. This receptor shows strong expression in epithelia cells and may be important in environmental diseases such as asthma.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Intramural Research (Z01)
Project #
1Z01ES090057-03
Application #
6106786
Study Section
Special Emphasis Panel (LST)
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost
City
State
Country
United States
Zip Code
Min, Jungki; Perera, Lalith; Krahn, Juno M et al. (2018) Probing Dominant Negative Behavior of Glucocorticoid Receptor ? through a Hybrid Structural and Biochemical Approach. Mol Cell Biol :
Jewell, Christine M; Cidlowski, John A (2007) Molecular evidence for a link between the N363S glucocorticoid receptor polymorphism and altered gene expression. J Clin Endocrinol Metab 92:3268-77
Lu, Nick Z; Collins, Jennifer B; Grissom, Sherry F et al. (2007) Selective regulation of bone cell apoptosis by translational isoforms of the glucocorticoid receptor. Mol Cell Biol 27:7143-60
Lewis-Tuffin, Laura J; Jewell, Christine M; Bienstock, Rachelle J et al. (2007) Human glucocorticoid receptor beta binds RU-486 and is transcriptionally active. Mol Cell Biol 27:2266-82
Duma, Danielle; Jewell, Christine M; Cidlowski, John A (2006) Multiple glucocorticoid receptor isoforms and mechanisms of post-translational modification. J Steroid Biochem Mol Biol 102:11-21
Tliba, Omar; Cidlowski, John A; Amrani, Yassine (2006) CD38 expression is insensitive to steroid action in cells treated with tumor necrosis factor-alpha and interferon-gamma by a mechanism involving the up-regulation of the glucocorticoid receptor beta isoform. Mol Pharmacol 69:588-96
Lu, Nick Z; Cidlowski, John A (2006) Glucocorticoid receptor isoforms generate transcription specificity. Trends Cell Biol 16:301-7
Lewis-Tuffin, Laura J; Cidlowski, John A (2006) The physiology of human glucocorticoid receptor beta (hGRbeta) and glucocorticoid resistance. Ann N Y Acad Sci 1069:1-9
Franco, Rodrigo; Cidlowski, John A (2006) SLCO/OATP-like transport of glutathione in FasL-induced apoptosis: glutathione efflux is coupled to an organic anion exchange and is necessary for the progression of the execution phase of apoptosis. J Biol Chem 281:29542-57
Panayiotidis, M I; Bortner, C D; Cidlowski, J A (2006) On the mechanism of ionic regulation of apoptosis: would the Na+/K+-ATPase please stand up? Acta Physiol (Oxf) 187:205-15

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