Skip Navigation



ToxSci Advance Access published online on November 20, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfl172
This Article
Right arrow Advance Access manuscript (PDF) Freely available
Right arrow All Versions of this Article:
96/1/83    most recent
kfl172v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Lin, H.
Right arrow Articles by Lee, T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lin, H.
Right arrow Articles by Lee, T.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© 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.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?




Disclaimer:
Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.