Roles of ER, SRC-1, and CBP Phosphorylation in Estrogen Receptor-Regulated Gene Expression
Abstract
Breast cancer patients who possess cancers that are estrogen-dependent usually respond well initially to the antiestrogen, tamoxifen. However, the cancer subsequently becomes resistant to tamoxifen, possibly through increases in cAMP and protein kinase A or through stimulation of the MAP kinase pathway, which have been associated with the conversion of the tamoxifen metabolite, 4-hydroxytamoxifen (4HT), into an estrogen receptor (ER) agonist. Tamoxifen resistance may also occur through cellular alterations in the balance of coactivators and corepressors. In this report, the contribution of phosphorylation and proteasome-mediated ER degradation to its transactivation function is explored. An inhibitor of the proteasome, MG132, interferes with ER function and blocks the agonist activity of 4HT. MG132 also stabilizes ER and prevents its ligand-mediated down-regulation. Phosphorylation-defective ER mutants were found to be more stable than the wild-type receptor suggesting that receptor phosphorylation plays a role in regulating its stability. Deletion of the N-terminal AB domain of ER results in a highly unstable truncated ER indicating that the N-terminus of the receptor may contribute to ER stability. These results expand upon the findings which may indicate a clinical use for proteasome inhibitors in blocking tamoxifen antagonist/agonist switching in women receiving long-term tamoxifen therapy.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 1999
- Accession Number
- ADB251613
Entities
People
- David M. Lonard
Organizations
- Baylor College of Medicine