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Published on: May 7, 2018
A novel estrogen receptor intramolecular folding-based titratable transgene expression system
Ramasamy Paulmurugan1, Parasuraman Padmanabhan, Byeong-Cheol Ahn
1Department of Radiology, Stanford University School of Medicine, James H. Clark Center, 318 Campus Drive, 150 East Wing, 1st Floor, Stanford, CA 94305-5427, USA. paulmur8@stanford.edu
A novel gene expression system using estrogen receptor (ER) structural changes allows precise control of gene activity. This adaptable system shows promise for gene therapy, drug screening, and studying gene regulation in living organisms.
Area of Science:
- Molecular Biology
- Gene Therapy
- Biotechnology
Background:
- Regulated gene expression is crucial for effective gene therapy.
- Estrogen receptor (ER) ligand-induced structural changes offer a basis for novel regulatory systems.
Purpose of the Study:
- To develop and characterize a novel ligand-induced transcriptional activation system based on intramolecular folding of the estrogen receptor (ER).
- To demonstrate the system's utility in titrating gene expression and its application in gene therapy and biological studies.
Main Methods:
- Constructed ER variants (GAL4(DBD)-ER-VP16) to study ligand-regulated transactivation.
- Utilized ER ligands and a mutant ER (G521T) for specific activation.
- Tested the system's therapeutic efficiency using the p53 protein in cell cultures and animal models.
Main Results:
- Demonstrated efficient ligand-regulated transactivation with various ER ligands.
- Developed a bidirectional system for titrating reporter and therapeutic gene expression.
- Showcased successful raloxifene-induced activation in mice using a mutant ER, independent of endogenous estradiol.
- Validated the system's efficacy in controlling p53 expression for potential gene therapy.
Conclusions:
- The developed ER-based system offers precise, ligand-inducible control over gene expression.
- This versatile system has broad applications in gene therapy, ER biology research, and drug discovery.
