Gene Activation by Antiestrogens Used in Breast Cancer Therapy Via the Interaction of Estrogen Receptor and AP-1.
Annual rept. 1 Jul 95-30 Jun 96,
CALIFORNIA UNIV SAN FRANCISCO
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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.
- Genetic Engineering and Molecular Biology
- Anatomy and Physiology
- Medicine and Medical Research
- Organic Chemistry
- Polymer Chemistry