Functional blockade of Smad4 leads to a decrease in beta-catenin levels and signaling activity in human pancreatic carcinoma cells.
In the last several years, many laboratories have tried to unravel the complex signaling mechanisms activated by TGF-beta(1) in transformed cells. Smad proteins are the principal mediators of the transforming growth factor beta (TGF-beta) 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 beta-catenin. Moreover, loss of Smad4 abrogated beta-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-beta(1)/Smad2,3-signaling activity, the above-mentioned effects of Smad4 on beta-catenin stability were independent of the TGF-beta1/Smad2,3-signaling pathway. These findings provide evidence for a cross talk between Smad4 and the Wnt/beta-catenin pathway in pancreatic carcinoma cells, suggesting a new role for Smad4 as an attenuator of beta-catenin proteasomal degradation.
Romero
Diana
D
Instituto de Investigaciones Biomedicas Alberto Sols, Arturo Duperier 4, 28029 Madrid, Spain. romerd@mmc.org
Iglesias
Maite
M
Vary
Calvin P H
CP
Quintanilla
Miguel
M
D000818:Animals; D045744:Cell Line, Tumor; D011905:Genes, ras / Q000187:drug effects; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms; D012334:RNA, Neoplasm / Q000187:drug effects / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D051901:Smad4 Protein / Q000037:antagonists & inhibitors*; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014183:Transplantation, Heterologous; D051176:beta Catenin / Q000502:physiology*
D012334:RNA, Neoplasm; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D016212:Transforming Growth Factor beta; D051176:beta Catenin