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Title

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

AuthorsRomero, Diana; Iglesias, Maite; Vary, Calvin P. H.; Quintanilla, Miguel CSIC ORCID
Issue Date2008
PublisherOxford University Press
CitationCarcinogenesis 29(5): 1070-1076 (2008)
AbstractIn 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. © The Author 2008. Published by Oxford University Press. All rights reserved.
DescriptionEl pdf del artículo es la versión de autor.
Publisher version (URL)http://dx.doi.org/10.1093/carcin/bgn054
URIhttp://hdl.handle.net/10261/81914
DOI10.1093/carcin/bgn054
Identifiersdoi: 10.1093/carcin/bgn054
issn: 0143-3334
e-issn: 1460-2180
Appears in Collections:(IIBM) Artículos

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