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Estrogen receptor alpha and Sp1 regulate progesterone receptor gene expression
Jennifer R Schultz1, Larry N Petz, Ann M Nardulli
1Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, 524 Burrill Hall, 407 South Goodwin Avenue, 61801, USA.
Molecular and Cellular Endocrinology
|April 23, 2003
Summary
Estrogen induces the progesterone receptor (PR) gene via Sp1 sites, even without a direct estrogen response element. Estrogen receptor alpha (ERalpha) enhances Sp1 binding to the PR gene, driving estrogen responsiveness.
Area of Science:
- Molecular Endocrinology
- Gene Regulation
- Cancer Biology
Background:
- The progesterone receptor (PR) gene is upregulated by estrogen in reproductive tissues, mammary glands, and breast cancer cells.
- The human PR gene lacks a canonical estrogen response element (ERE), suggesting an alternative mechanism for estrogen induction.
Purpose of the Study:
- To identify the specific DNA region and transcription factors responsible for estrogen-induced PR gene expression.
- To elucidate the mechanism by which estrogen receptor alpha (ERalpha) mediates this estrogen responsiveness.
Main Methods:
- Reporter gene assays using a heterologous promoter linked to the -80/-34 region of the PR gene.
- Electrophoretic mobility shift assays (EMSAs) to assess Sp1 and ERalpha binding to the identified PR gene region.
- Site-directed mutagenesis of Sp1 binding sites within the -80/-34 region.
Main Results:
- A region from -80 to -34 of the human PR gene, containing two Sp1 sites, confers estrogen and ERalpha-dependent responsiveness.
- Both nuclear Sp1 and purified Sp1 bind to these sites, with preferential binding to the proximal Sp1 site.
- Mutation of either Sp1 site reduces Sp1-DNA complex formation and ERalpha-mediated transactivation, indicating their importance.
- ERalpha enhances Sp1 binding to the PR gene promoter but does not directly interact with the -80/-34 region.
Conclusions:
- Estrogen receptor alpha (ERalpha) confers estrogen inducibility to the progesterone receptor (PR) gene by enhancing the interaction of Sp1 transcription factor with specific Sp1 sites in the proximal promoter region.
- This mechanism of indirect regulation highlights the complex interplay between transcription factors and nuclear receptors in controlling gene expression.