Cellular toxicity induced by SRF-mediated transcriptional squelching
Huey Lin1, Jami McGrath, Ping Wang
1Department of Biochemistry, SUNY at Buffalo, Buffalo, New York 14214, USA.
Summary
High levels of serum response factor (SRF) cause cell death through transcriptional squelching, offering a potential strategy for cancer therapy. This SRF-mediated cell killing is potent and targets various cell types.
Area of Science:
- Molecular Biology
- Cell Biology
- Toxicology
Background:
- Serum response factor (SRF) is a key transcriptional activator involved in embryonic development, cell growth, and myogenesis.
- SRF possesses potent transcriptional activation domains that can cause "transcriptional squelching" at high expression levels, interfering with gene expression.
Purpose of the Study:
- To characterize the toxicological aspects of SRF-mediated transcriptional squelching.
- To investigate the potential of SRF transcriptional squelching as a cancer therapeutic strategy.
Main Methods:
- Utilized an adenoviral expression system to achieve up to a 50-fold increase in SRF protein levels.
- Investigated SRF localization, promoter interaction independence, and cell killing mechanisms across various cell types.
- Compared SRF-mediated cell killing with that of p53 and analyzed the roles of SRF domains and apoptotic pathways.
Main Results:
- Overexpressed SRF localized to the nucleus and induced transcriptional squelching, independent of specific promoter interactions.
- SRF-mediated squelching caused robust cell killing in normal, abnormal proliferating, and postmitotic cells, exceeding p53-mediated cell death.
- Only the transcriptional activation domain of SRF was required for cell killing, and this process was independent of serum withdrawal and resistant to caspase/calpain inhibition and Bcl-xL overexpression.
Conclusions:
- SRF-mediated transcriptional squelching is a potent mechanism for cell killing, affecting diverse cell types.
- The SRF gene represents a novel molecular target for cancer therapeutics, with potential for engineered cancer cell killing.
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