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ToxSci Advance Access originally published online on November 20, 2006
Toxicological Sciences 2007 96(1):83-91; 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

Cellular Toxicity Induced by SRF-Mediated Transcriptional Squelching

Huey Lin, Jami McGrath, Ping Wang and Techung Lee1

Department of Biochemistry, SUNY at Buffalo, Buffalo, New York 14214

1 To whom correspondence should be addressed at Department of Biochemistry, SUNY at Buffalo, 3435 Main Street, Buffalo, NY 14214. Fax: (716) 829-3106. E-mail: chunglee{at}buffalo.edu.

Received September 25, 2006; accepted November 14, 2006


  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 potent transcriptional activation domains 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 cytomegalovirus 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 postmitotic 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 cannot be effectively attenuated by blocking the caspase and calpain proteolytic pathways or by overexpression of the antiapoptotic 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.

Key Words: SRF; squelching; cellular toxicity.


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