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Carcinogenesis Advance Access originally published online on February 28, 2008
Carcinogenesis 2008 29(5):1070-1076; doi:10.1093/carcin/bgn054
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Functional blockade of Smad4 leads to a decrease in β-catenin levels and signaling activity in human pancreatic carcinoma cells

Diana Romero1,2,*, Maite Iglesias3, Calvin P.H. Vary2 and Miguel Quintanilla1

1 Instituto de Investigaciones Biomedicas Alberto Sols, Arturo Duperier 4, 28029 Madrid, Spain
2 Center for Molecular Medicine, Maine Medical Center Research Institute, 81 Research Drive, Scarborough, ME 04074, USA
3 Departamento de Bioquimica, Universidad Francisco de Vitoria, Ctra Pozuelo-Majadahonda km 1800, 28223 Pozuelo de Alarcon, Madrid, Spain

* To whom correspondence should be addressed. Tel: +1 (207) 885 8272; Fax: +1 (207) 885 8179; Email: romerd{at}mmc.org

In the last several years, many laboratories have tried to unravel the complex signaling mechanisms activated by TGF-β1 in transformed cells. Smad proteins are the principal mediators of the transforming growth factor β (TGF-β) response, but this factor can also activate Smad-independent pathways in different cell types. Our previous studies in murine keratinocytes led to the identification of a cooperation between oncogenic Ras and Smad4 inactivation during malignant progression. We further investigated the function of Smad4 in human pancreatic cancer, in which loss-of-function mutations affecting Smad4 occur with a 50% frequency. Expression of a dominant-negative Smad4 construct in the adenocarcinoma cell line PANC-1 led to increased ubiquitination and proteasomal degradation of β-catenin. Moreover, loss of Smad4 abrogated β-catenin-signaling activity and was associated with a reduction of the tumorigenic potential of PANC-1 cells in scid mice. Although the expression of the dominant-negative Smad4 blocked TGF-β1/Smad2,3-signaling activity, the above-mentioned effects of Smad4 on β-catenin stability were independent of the TGF-β1/Smad2,3-signaling pathway. These findings provide evidence for a cross talk between Smad4 and the Wnt/β-catenin pathway in pancreatic carcinoma cells, suggesting a new role for Smad4 as an attenuator of β-catenin proteasomal degradation.

Abbreviations: APC, adenomatous polyposis coli; TGF-β, transforming growth factor β

Received August 10, 2007; revised February 1, 2008; accepted February 17, 2008.


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