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dc.contributor.author | Iglesias, Maite | - |
dc.contributor.author | Frontelo, Pilar | - |
dc.contributor.author | Gamallo, Carlos | - |
dc.contributor.author | Quintanilla, Miguel | - |
dc.date.accessioned | 2013-07-17T10:42:39Z | - |
dc.date.available | 2013-07-17T10:42:39Z | - |
dc.date.issued | 2000 | - |
dc.identifier | issn: 0950-9232 | - |
dc.identifier | e-issn: 1476-5594 | - |
dc.identifier.citation | Oncogene 19(36): 4134-4145 (2000) | - |
dc.identifier.uri | http://hdl.handle.net/10261/79810 | - |
dc.description | El pdf del artículo es la versión post-print. | - |
dc.description.abstract | 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. | - |
dc.description.sponsorship | This work was supported by grants: SAF98-0085-CO3-02 from the Comisión Interministerial de Ciencia y Tecnología (CICYT), and 8.1/22/97 from the Comunidad Autonoma de Madrid (CAM). | - |
dc.language.iso | eng | - |
dc.publisher | Nature Publishing Group | - |
dc.relation.isversionof | Postprint | - |
dc.rights | openAccess | - |
dc.title | 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 | - |
dc.type | artículo | - |
dc.relation.publisherversion | http://www.nature.com/onc/journal/v19/n36/full/1203764a.html | - |
dc.date.updated | 2013-07-17T10:42:39Z | - |
dc.description.version | Peer Reviewed | - |
dc.type.coar | http://purl.org/coar/resource_type/c_6501 | es_ES |
item.languageiso639-1 | en | - |
item.fulltext | With Fulltext | - |
item.openairecristype | http://purl.org/coar/resource_type/c_18cf | - |
item.cerifentitytype | Publications | - |
item.grantfulltext | open | - |
item.openairetype | artículo | - |
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Blockade of Smad4.pdf | 10,16 MB | Adobe PDF | Visualizar/Abrir |
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