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Targeting estrogen responsive elements (EREs): design of potent transactivators for ERE-containing genes
Jing Huang1, Xiaodong Li, Ping Yi
1Department of Biochemistry and Biophysics, University of Rochester School of Medicine and Dentistry, NY 14642, USA.
Molecular and Cellular Endocrinology
|May 8, 2004
Summary
Engineered estrogen responsive element-binding activators (EBAs) demonstrate the critical role of estrogen-responsive genes in cell proliferation. These novel transregulators offer new therapeutic strategies for estrogen-dependent cancers.
Area of Science:
- Molecular Biology
- Cell Biology
- Endocrinology
Background:
- Estrogen hormone (E2) and its receptors (ER alpha and beta) regulate target tissue physiology and pathophysiology.
- E2-ER complex mediates genomic and non-genomic events, influencing cell proliferation and differentiation.
- Estrogen-responsive element (ERE)-dependent signaling is crucial for gene expression, but its role in cell proliferation requires further elucidation.
Purpose of the Study:
- To investigate the importance of ERE-dependent E2-ER signaling in cell proliferation.
- To engineer novel ERE-binding activators (EBAs) for precise regulation of ERE-containing genes.
Main Methods:
- Engineered modular ERE-binding activators (EBAs) by joining DNA-binding domains with a hinge domain.
- Integrated strong activation domains to create constitutively active EBAs.
- Assessed EBA-induced gene expression and effects on cell cycle progression in breast cancer cell lines.
Main Results:
- EBAs robustly induced ERE-containing promoter constructs independently of ligand, dimerization, ER subtype, or status.
- EBAs altered cell cycle progression in breast cancer cells, mimicking E2-ER effects.
- Demonstrated the significant role of ERE-containing genes in regulating cell proliferation.
Conclusions:
- ERE-dependent signaling is critical for regulating cell proliferation.
- Engineered EBAs provide a tool for targeted gene regulation and identifying estrogen-responsive gene networks.
- EBAs hold potential for developing novel therapeutic strategies for estrogen-target tissue cancers.