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Título: | Blockade of Smad4 in transformed keratinocytes containing a Ras oncogene leads to hyperactivation of the Ras-dependent Erk signalling pathway associated with progression to undifferentiated carcinomas |
Autor: | Iglesias, Maite; Frontelo, Pilar; Gamallo, Carlos; Quintanilla, Miguel CSIC ORCID | Fecha de publicación: | 2000 | Editor: | Nature Publishing Group | Citación: | Oncogene 19(36): 4134-4145 (2000) | Resumen: | Smad4 functions as a transcription factor in TGF-β signalling. We have investigated the role of Smad4 in the TGF-β1 cell responses of transformed PDV keratinocytes, which contain a Ras oncogene, and of non-tumorigenic MCA3D keratinocytes, by transfecting both cell lines with a dominant-negative Smad4 construct. Smad4 mediates TGF-β1-induced up-regulation of p21(Cip1) and growth arrest in MCA3D cells. However, in PDV keratinocytes, Smad4 is only partially involved in TGF-β1-induced growth inhibition, and does not mediate enhancement of p21(Cip1) levels by the growth factor. TGF-β1 activates Ras/Erk signalling activity in both cell lines. PD098059, a specific inhibitor of MEK, disminishes TGF-β1-induced p21(Cip1) levels in PDV but not in MCA3D cells, suggesting an involvement of Erk in upregulation of p21(Cip1) by TGF-β1 in PDV cells. PDV dominant-negative Smad4 cell transfectants, but not MCA3D transfectants, showed constitutive hyperactivation of the Ras/Erk signalling pathway, increased secretion of urokinase, higher motility properties, and a change to a fibroblastoid cell morphology associated in vivo with the transition from a well differentiated to a poorly differentiated tumour phenotype. Infection of MCA3D control and dominant negative Smad4 cell transfectants with retroviruses carrying a Ras oncogene led to enhanced p21(Cip1) and urokinase secreted levels, independently of TGF-β1 stimulation, that were reduced by PD098059. These results suggest that Smad4 acts inhibiting Ras-dependent Erk signalling activity in Ras-transformed keratinocytes. Loss of Smad4 function in these cells results in hyperactivation of Erk signalling and progression to undifferentiated carcinomas. | Descripción: | El pdf del artículo es la versión post-print. | Versión del editor: | http://www.nature.com/onc/journal/v19/n36/full/1203764a.html | URI: | http://hdl.handle.net/10261/79810 | Identificadores: | issn: 0950-9232 e-issn: 1476-5594 |
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