Source:http://linkedlifedata.com/resource/pubmed/id/10962574
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
36
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| pubmed:dateCreated |
2000-10-2
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| pubmed:abstractText |
Smad4 functions as a transcription factor in TGF-beta signalling. We have investigated the role of Smad4 in the TGF-beta1 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-beta1-induced up-regulation of p21Cip1 and growth arrest in MCA3D cells. However, in PDV keratinocytes, Smad4 is only partially involved in TGF-beta1-induced growth inhibition, and does not mediate enhancement of p21Cip1 levels by the growth factor. TGF-beta1 activates Ras/Erk signalling activity in both cell lines. PD098059, a specific inhibitor of MEK, disminishes TGF-beta1-induced p21Cip1 levels in PDV but not in MCA3D cells, suggesting an involvement of Erk in up-regulation of p21Cip1 by TGF-beta1 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 p21Cip1 and urokinase secreted levels, independently of TGF-beta1 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. Oncogene (2000) 19, 4134 - 4145
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| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Cdkn1a protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclin-Dependent Kinase Inhibitor...,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclins,
http://linkedlifedata.com/resource/pubmed/chemical/DNA-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Mitogen-Activated Protein Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Smad4 Protein,
http://linkedlifedata.com/resource/pubmed/chemical/Smad4 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Trans-Activators,
http://linkedlifedata.com/resource/pubmed/chemical/Transforming Growth Factor beta,
http://linkedlifedata.com/resource/pubmed/chemical/Urokinase-Type Plasminogen Activator,
http://linkedlifedata.com/resource/pubmed/chemical/ras Proteins
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| pubmed:status |
MEDLINE
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| pubmed:month |
Aug
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| pubmed:issn |
0950-9232
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| pubmed:author | |
| pubmed:issnType |
Print
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| pubmed:day |
24
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| pubmed:volume |
19
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
4134-45
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| pubmed:dateRevised |
2009-11-19
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| pubmed:meshHeading |
pubmed-meshheading:10962574-Animals,
pubmed-meshheading:10962574-Blotting, Western,
pubmed-meshheading:10962574-Carcinoma,
pubmed-meshheading:10962574-Cell Line, Transformed,
pubmed-meshheading:10962574-Cyclin-Dependent Kinase Inhibitor p21,
pubmed-meshheading:10962574-Cyclins,
pubmed-meshheading:10962574-DNA-Binding Proteins,
pubmed-meshheading:10962574-Enzyme Activation,
pubmed-meshheading:10962574-Fluorescent Antibody Technique,
pubmed-meshheading:10962574-Keratinocytes,
pubmed-meshheading:10962574-Mice,
pubmed-meshheading:10962574-Mice, Nude,
pubmed-meshheading:10962574-Mitogen-Activated Protein Kinases,
pubmed-meshheading:10962574-Signal Transduction,
pubmed-meshheading:10962574-Skin Neoplasms,
pubmed-meshheading:10962574-Smad4 Protein,
pubmed-meshheading:10962574-Trans-Activators,
pubmed-meshheading:10962574-Transfection,
pubmed-meshheading:10962574-Transforming Growth Factor beta,
pubmed-meshheading:10962574-Up-Regulation,
pubmed-meshheading:10962574-Urokinase-Type Plasminogen Activator,
pubmed-meshheading:10962574-ras Proteins
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| pubmed:year |
2000
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| pubmed:articleTitle |
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.
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| pubmed:affiliation |
Instituto de Investigaciones Biomédicas Alberto Sols CSIC-UAM, Arturo Duperier 4, 28029-Madrid, Spain.
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| pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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