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In the last several years, many laboratories have tried to unravel the complex signaling mechanisms activated by TGF-β  1  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-β  1  /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.

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