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Molecular and Cellular Biology, September 2005, p. 8108-8125, Vol. 25, No. 18
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.18.8108-8125.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Smad4 Dependency Defines Two Classes of Transforming Growth Factor ß (TGF-ß) Target Genes and Distinguishes TGF-ß-Induced Epithelial-Mesenchymal Transition from Its Antiproliferative and Migratory Responses{dagger}

Laurence Levy and Caroline S. Hill*

Laboratory of Developmental Signalling, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom

Received 19 April 2005/ Returned for modification 23 May 2005/ Accepted 24 June 2005

In response to transforming growth factor ß (TGF-ß), Smad4 forms complexes with activated Smad2 and Smad3, which accumulate in the nucleus, where they both positively and negatively regulate TGF-ß target genes. Mutation or deletion of Smad4 is found in about 50% of pancreatic tumors and in about 15% of colorectal tumors. As Smad4 is a central component of the TGF-ß/Smad pathway, we have determined whether Smad4 is absolutely required for all TGF-ß responses, to evaluate the effect of its loss during human tumor development. We have generated cell lines from the immortalized human keratinocyte cell line HaCaT or the pancreatic tumor cell line Colo-357, which stably express a tetracyline-inducible small interfering RNA targeted against Smad4. In response to tetracycline, Smad4 expression is effectively silenced. Large-scale microarray analysis identifies two populations of TGF-ß target genes that are distinguished by their dependency on Smad4. Some genes absolutely require Smad4 for their regulation, while others do not. Functional analysis also indicates a differential Smad4 requirement for TGF-ß-induced functions; TGF-ß-induced cell cycle arrest and migration, but not epithelial-mesenchymal transition, are abolished after silencing of Smad4. Altogether our results suggest that loss of Smad4 might promote TGF-ß-mediated tumorigenesis by abolishing tumor-suppressive functions of TGF-ß while maintaining some tumor-promoting TGF-ß responses.

* Corresponding author. Mailing address: Laboratory of Developmental Signalling, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom. Phone: 44-20-7269-2941. Fax: 44-20-7269-3093. E-mail: caroline.hill{at}cancer.org.uk.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, September 2005, p. 8108-8125, Vol. 25, No. 18
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.18.8108-8125.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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