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ToxSci Advance Access published online on September 8, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfi310
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© The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received July 27, 2005
Accepted August 29, 2005

Systems Toxicology

Tsc2 Expression Increases the Susceptibility of Renal Tumor Cells to Apoptosis

Todd M. Kolb 1, Ling Duan 1, and Myrtle A. Davis 2*

1 Program in Toxicology and Department of Pathology, University of Maryland, School of Medicine, Baltimore, MD 21201
2 Toxicology and Drug Disposition, Lilly Research Laboratories, Eli Lilly and Company, Greenfield, IN 46140

* To whom correspondence should be addressed.
Myrtle A. Davis, E-mail: davisma{at}lilly.com


  Abstract

Although the precise role for the tuberous sclerosis complex-2 tumor suppressor gene (Tsc2) in tumor suppression is not clear, many studies have implicated Tsc2 in the regulation of cell differentiation, cell cycle control, GTPase activity, transcription, polycystin-1 localization, and translation initiation. We propose that Tsc2 also increases susceptibility to apoptosis, and that this functional role may contribute to the tumor suppressor activity of Tsc2. We previously characterized the apoptotic response of a Tsc2-null renal tumor cell line (ERC-18) to the tumor promoter okadaic acid (OKA). In the present study, we expressed Tsc2 in ERC-18 cells and compared the effect of Tsc2 expression on apoptotic induction. Tsc2 expression increased the susceptibility of ERC-18 cells to apoptosis induced by OKA and the phosphatidylinositol-3' kinase inhibitor, LY294002. In addition, Tsc2 expression abrogated OKA-induced cell detachment of ERC-18 cells. These results indicate that the OKA-induced, caspase-independent detachment previously observed in ERC-18 cells is Tsc2-dependent, and may support an additional role for the Tsc2 in regulating cell adhesion.

Keywords: tumorigenesis; Tsc2; apoptosis; okadaic acid.
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