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Two glucocorticoid binding sites on the human glucocorticoid receptor
1Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch, Galveston 77550.
Endocrinology
|October 1, 1990
Summary
Cortivazol (CVZ), a potent synthetic glucocorticoid, exhibits unique binding to the glucocorticoid receptor (GR) in leukemic cells, suggesting dual binding sites. This offers new therapeutic avenues for glucocorticoid-resistant leukemia.
Area of Science:
- Endocrinology
- Molecular Biology
- Cancer Research
Background:
- Glucocorticoids induce lytic effects in leukemic cells through glucocorticoid receptor (GR) interactions.
- Standard glucocorticoids bind to GR with one-site kinetics.
- Cortivazol (CVZ) is a high-potency synthetic glucocorticoid with unique binding properties.
Purpose of the Study:
- To investigate the nature of the higher affinity CVZ binding site.
- To understand the mechanism behind CVZ's enhanced biological effects in leukemic cells.
- To explore CVZ's potential in overcoming dexamethasone resistance.
Main Methods:
- Binding assays using CEM C7 and IM-9 cell lines.
- Utilizing the antiglucocorticoid RU 38486 to block CVZ binding sites.
- Immunological characterization of CVZ binding proteins.
- Analysis of CVZ-resistant leukemic cell clones.
Main Results:
- CVZ demonstrated multi-site binding in both CEM C7 and IM-9 cell lines.
- RU 38486 inhibited both high and low affinity CVZ binding sites.
- All CVZ binding sites were identified on proteins indistinguishable from the human GR.
- CVZ-resistant cells showed a complete loss of CVZ binding sites.
Conclusions:
- CVZ recognizes two distinct binding sites on the human glucocorticoid receptor (GR) or a closely related protein.
- These dual binding sites contribute to CVZ's enhanced potency and efficacy.
- The findings suggest CVZ as a promising therapeutic agent for glucocorticoid-resistant leukemias.