Discovery of a novel mechanism of steroid receptor antagonism: WAY-255348 modulates progesterone receptor cellular localization and promoter interactions
| Autor: | Matthew R. Yudt, Elizabeth Haglund, Scott A. Jelinsky, Louise A. Russo, Sunil Nagpal, Andrew Fensome, Raymond J. Unwalla, Jeffrey Cohen, Thomas J. Berrodin, Zhiming Zhang, Debra Ellis, Richard C. Winneker, Neil Cooch, Jay Wrobel |
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| Rok vydání: | 2011 |
| Předmět: |
Models
Molecular Chromatin Immunoprecipitation Indoles Protein Conformation Nuclear Receptor Coactivators Active Transport Cell Nucleus Biology Biochemistry Binding Competitive Radioligand Assay Cell Line Tumor Progesterone receptor Humans Pyrroles Phosphorylation Receptor Promoter Regions Genetic Cellular localization Pharmacology Cell Nucleus Cell biology Drug Partial Agonism Nuclear receptor Signal transduction Antagonism Receptors Progesterone Co-Repressor Proteins Nuclear localization sequence |
| Zdroj: | Biochemical pharmacology. 82(11) |
| ISSN: | 1873-2968 |
| Popis: | WAY-255348 is a potent nonsteroidal progesterone receptor (PR) antagonist previously characterized in rodents and nonhuman primates. This report describes the novel mechanism by which WAY-255348 inhibits the activity of progesterone. Most PR antagonists bind to and block PR action by inducing a unique “antagonist” conformation of the PR. However, WAY-255348 lacks the bulky side chains or chemical groups that have been associated with the conformation changes of helix 12 that lead to functional antagonism. We show that WAY-255348 achieves antagonist activity by binding to and subsequently preventing progesterone-induced nuclear accumulation, phosphorylation and promoter interactions of the PR. This effect was concentration dependent, as high concentrations of WAY-255348 alone are able to induce nuclear translocation, phosphorylation and subsequent promoter interactions resulting in partial agonist activity at these concentrations. However, at lower concentrations where nuclear accumulation and phosphorylation are prevented, the progesterone-induced DNA binding is blocked along with PR-dependent gene expression. Analysis of the PR conformation induced by WAY-255348 using a limited protease digestion assay, suggested that the WAY-255348 bound PR conformation was similar to that of a progesterone agonist-bound PR and distinct from steroidal antagonist-bound PR conformations. Furthermore, the recruitment and binding of peptides derived from nuclear receptor co-activators is consistent with WAY-255348 inducing an agonist-like conformation. Taken together, these data suggest that WAY-255348 inhibits PR action through a novel molecular mechanism that is distinct from previously studied PR modulators and may be a useful tool to further understanding of PR signaling pathways. Development of therapeutic molecules with this ‘passive’ antagonism mechanism may provide distinct advantages for patients with reproductive disorders or PR positive breast cancers. |
| Databáze: | OpenAIRE |
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