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Molecular and Cellular Biology, September 2004, p. 7559-7566, Vol. 24, No. 17
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.17.7559-7566.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Aberrant Expression of the Transcription Factors Snail and Slug Alters the Response to Genotoxic Stress

Masahiro Kajita,1 Karissa N. McClinic,1,2 and Paul A. Wade1,2*

Department of Pathology and Laboratory Medicine, Winship Cancer Institute,1 Graduate Program in Genetics and Molecular Biology, Emory University School of Medicine, Atlanta, Georgia2

Received 2 April 2004/ Returned for modification 3 May 2004/ Accepted 3 June 2004

Snail and Slug are closely related transcriptional repressors involved in embryonic patterning during metazoan development. In human cancer, aberrant expression of Snail and/or Slug has been correlated with invasive growth potential, a property primarily attributed to their ability to directly repress transcription of genes whose products are involved in cell-cell adhesion, such as E-cadherin, occludin, and claudins. To investigate the molecular mechanisms of alterations in epithelial cell fate mediated by aberrant expression of Snail or Slug, we analyzed the consequences of exogenous expression of these factors in human cancer cells. Aberrant expression of either Snail or Slug led to changes in cell morphology, the loss of normal cell-cell contacts, and the acquisition of invasive growth properties. Snail or Slug expression also promoted resistance to programmed cell death elicited by DNA damage. Detailed molecular analysis revealed direct transcriptional repression of multiple factors with well-documented roles in programmed cell death. Depletion of endogenous Snail by RNA interference led to increased sensitivity to DNA damage accompanied by increased expression of the proapoptotic factors identified as targets of Snail. Thus, aberrant expression of Snail or Slug may promote tumorigenesis through increased resistance to programmed cell death.

* Corresponding author. Mailing address: Emory University, Department of Pathology, Whitehead Bldg., Rm. 142, 615 Michael St., Atlanta, GA 30322. Phone: (404) 712-9666. Fax: (404) 727-8538. E-mail: pwade{at}emory.edu.

Molecular and Cellular Biology, September 2004, p. 7559-7566, Vol. 24, No. 17
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.17.7559-7566.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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