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Stress Potentiation of Glucocorticoid Receptor Transactivity Through HSF1-dependent and HSF1-independent Pathways
| Title: | Stress Potentiation of Glucocorticoid Receptor Transactivity Through HSF1-dependent and HSF1-independent Pathways |
| Author: | Jones, Thomas Joseph |
| Description: | Stress potentiation of glucocorticoid receptor (GR) transcription enhancement activity (transactivity) has been seen in response to heat shock (HS) at 43˚C or chemical shock (CS) with 200 µM sodium arsenite. Under these conditions, a robust increase in GR transactivity is observed using GR-responsive promoters. Early work has suggested a role for heat shock factor 1 (HSF1) in the stress potentiation effect. To provide conclusive evidence for this role, a constitutively-active mutant of HSF1 (E189) was used. Results show that expression of E189, in the absence of stress, causes both an increase in heat shock protein expression and in GR transactivity. Further, this potentiation approached the levels observed under HS conditions, providing evidence that stress potentiation of GR activity occurs, at least in part, through HSF1-controlled gene products. To expand the roles of stress signaling in GR activity, we investigated the ability of unstressed cells to respond to stress-conditioned cell culture media. Control- and stress-conditioned media were transferred from L929 cells to adjacent unstressed cells in the presence of dexamethasone. Conditioned media was harvested 4 and 20h post-stress treatment and transferred to L929 cells stably selected for the minimal GRE2E1B promoter controlling expression of CAT. Results provide evidence for stress-induced release of a factor (SRF) that has the ability to enhance GR transactivity. The SRF exhibited characteristics that were consistent with media-soluble proteins, but was unable to function in serum-free media to increase GR transactivation in unstressed cells. In summary, this work provides evidence for two mechanisms through which stress can regulate GR activity. One mechanism is stress-activated HSF1-dependent gene product(s) can directly or indirectly affect the ligand-dependent transactivity of the GR. The second mechanism is stress-induced release of SRF into the cell culture media can cause an increase in transactivity of the GR in identical unstressed cells, or potentially in both stressed and unstressed cells. The latter mechanism has implications for physiological responses to stress, suggesting an “early warning” mechanism in which stressed cells initiate preemptive GR protective pathways through release of SRF. |
| Permanent Link: |
http://rave.ohiolink.edu/etdc/view?acc_num=mco1085667689
http://hdl.handle.net/2374.OX/18035 |
| Date: | 2004 |
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