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Modulation of oestrogen receptor activity by oestrogens and anti-oestrogens
1Imperial Chemical Industries, Central Toxicology Laboratory, Macclesfield, Cheshire, England.
Abstract:
The oestrogen receptor is a member of a supergene family that includes receptors for steroid and thyroid hormones, vitamin D3, and retinoic acid. A number of additional members of the family have been cloned where the putative ligand remains to be identified. The oestrogen receptor is a ligand-activated transcription factor that modulates specific gene expression by binding to short DNA sequences (oestrogen response elements) located in the vicinity of oestrogen-regulated genes. Regions of the receptor responsible for hormone-binding. DNA-binding and activation of transcription, have been identified. The anti-oestrogen, tamoxifen (Nolvadex), behaves as a weak oestrogen agonist. A model, based upon our current understanding of the molecular mechanism of oestrogen action, will be presented to explain the cell and gene specific effects of some anti-oestrogens.
Insights
The oestrogen receptor (ER) is a transcription factor regulating gene expression. Tamoxifen, an anti-oestrogen, acts as a weak ER agonist, with its effects explained by a molecular model.
Area of Science:
- Molecular Endocrinology
- Genetics
- Pharmacology
Background:
- The oestrogen receptor (ER) belongs to a supergene family, acting as a ligand-activated transcription factor.
- ER modulates gene expression by binding to oestrogen response elements in DNA.
- Other family members exist with unidentified ligands.
Purpose of the Study:
- To identify regions of the ER responsible for hormone-binding, DNA-binding, and transcriptional activation.
- To present a model explaining the cell and gene-specific effects of anti-oestrogens like tamoxifen.
Main Methods:
- Identification of functional regions within the oestrogen receptor.
- Development of a molecular model for oestrogen action and anti-oestrogen effects.
Main Results:
- Specific regions of the ER mediating hormone-binding, DNA-binding, and transcriptional activation have been identified.
- Tamoxifen (Nolvadex) exhibits weak oestrogen agonist activity.
Conclusions:
- A molecular model elucidates the mechanism of oestrogen action.
- This model explains the complex, cell-specific effects of anti-oestrogens on gene expression.