Gene Activation by Antiestrogens Used in Breast Cancer Therapy Via the Interaction of Estrogen Receptor and AP-1.
Abstract
Tamoxifen-liganded estrogen receptor (ER) activates target genes regulated by AP-1 sites in uterine cells, an action that may underlie the estrogen-like side effects of tamoxifen. We tested the ER functions needed for this AP-l pathway. Point mutations in the ER AF-l or AF-2 interfere with ER action at a classical estrogen response element (ERE), but do not hinder tamoxifen action at AP-l reporter genes. Similarly a point mutation that blocks ER dimerization is without effect on an AP-1 target. Deletion of the ER hinge region, which contains nuclear localization functions, blocks tamoxifen, but not estrogen action at AP-1. Although deletion of the DNA binding domain blocks tamoxifen action at AP-1, substitution of this domain with the DNA binding domain of the yeast GAL4 protein leaves tamoxifen activation of AP-1 targets. These results indicate that transcriptional activation, dimerization, and ERE binding functions of the ER are not needed for the tamoxifen-AP-1 pathway, and they reinforce the notion that this pathway operates by protein-protein interactions.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 1996
- Accession Number
- ADB216187
Entities
People
- Peter J. Kushner
Organizations
- University of California, San Francisco