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ToxSci Advance Access published online on November 20, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfl172
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received September 25, 2006
Accepted November 14, 2006

Genetic Toxicology

Cellular Toxicity Induced by SRF-Mediated Transcriptional Squelching

Huey Lin 1, Jami McGrath 1, Ping Wang 1, and Techung Lee 1 *

1 Department of Biochemistry, SUNY at Buffalo, Buffalo, NY 14214, USA

* To whom correspondence should be addressed.
Techung Lee, E-mail: chunglee{at}buffalo.edu


  Abstract

The transcriptional activator serum response factor (SRF) is a member of the immediate early gene family known to promote embryonic development, cell growth, and myogenesis through interaction with multiple nuclear protein factors. Previous studies have shown that SRF possesses a potent transcriptional activation domain(s) that can interfere with gene expression at artificially high expression levels through "transcriptional squelching". The current work sought to characterize toxicological aspects of SRF-mediated transcriptional squelching. An adenoviral expression system driven by the potent CMV promoter was used to achieve up to a 50-fold increase in SRF protein levels. The overexpressed SRF is nuclear localized and interferes with gene expression independent of specific promoter interaction as expected for transcriptional squelching. SRF-mediated squelching elicits robust cell killing affecting multiple cell types including normal and abnormal proliferating cells as well as post-mitotic cells such as cardiomyocytes in culture, and the cell killing is more pronounced than that mediated by the tumor suppressor protein p53. Although both the DNA-binding and transcriptional activation domains of SRF are normally required for the physiological roles of SRF, only the transcriptional activation domain is required for cell killing. Unlike c-myc-induced cell killing, squelching-induced cell death does not require serum withdrawal, and can not be effectively attenuated by blocking the caspase and calpain proteolytic pathways or by overexpression of the anti-apoptotic gene bcl-xL. These findings suggest transcriptional squelching may be engineered for killing cancer cells, and the SRF gene may represent a novel molecular target for cancer therapeutics.


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