Source:http://linkedlifedata.com/resource/pubmed/id/11118062
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
23
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| pubmed:dateCreated |
2000-12-12
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| pubmed:abstractText |
The position of the point mutation in the c-K-ras gene appears associated with different degrees of aggressiveness in human colorectal tumors. In addition, colon tumors carrying K-ras codon 12 mutations associate with lower levels of apoptosis than tumors lacking this mutation. To test the hypothesis of a distinct transforming capacity of different K-ras forms in an in vitro system, we generated stable transfectants of NIH3T3 cells expressing a plasmid containing K-ras mutated at codon 12 (K12) or at codon 13 (K13), or overexpressing the K-ras proto-oncogene (Kwt-oe). We evaluated changes in morphology, proliferative capacity, contact inhibition, and predisposition to apoptosis and anchorage-independent growth in K12, K13, and Kwt-oe transformants. In addition, we studied alterations in expression and/or activation of proteins that participate in signal transduction downstream of Ras or are involved in the regulation of apoptosis and cell-cell (E-cadherin and beta-catenin) and cell-substrate (focal adhesion kinase) interactions. We observed that K13 or Kwt-oe transformants died synchronically 24-48 h after reaching confluency. Their death was apoptotic. In contrast, K12 grew, forming bigger colonies with higher cell densities; and before reaching confluency, spontaneously formed spheroids and showed no sign of apoptosis. The enhanced resistance to apoptosis, loss of contact inhibition, and predisposition to anchorage-independent growth in the K12 transformants were associated with higher AKT/protein kinase B activation, bcl-2, E-cadherin, beta-catenin, and focal adhesion kinase overexpression, and RhoA underexpression, whereas the increased sensitivity of K13 or Kwt-oe transformants to apoptosis was associated with increased activation of the c-Jun-NH2-terminal kinase 1 pathway. All transformants showed a similar overactivation of mitogen-activated protein kinases and levels of bax expression similar to the endogenous level. Therefore, in our in vitro model, the localization of the mutation in the K-ras gene predisposes to a different level of aggressiveness in the transforming phenotype. K12 may increase aggressiveness not by altering proliferative pathways, but by the differential regulation of K-Ras downstream pathways that lead to inhibition of apoptosis, enhanced loss of contact inhibition, and increased predisposition to anchorage-independent growth. These results offer a molecular explanation for the increased aggressiveness of the tumors with K-ras codon 12 mutations observed in the clinical setting.
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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/Cadherins,
http://linkedlifedata.com/resource/pubmed/chemical/Catnb protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Codon,
http://linkedlifedata.com/resource/pubmed/chemical/Cytoskeletal Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Focal Adhesion Kinase 1,
http://linkedlifedata.com/resource/pubmed/chemical/Focal Adhesion Protein-Tyrosine...,
http://linkedlifedata.com/resource/pubmed/chemical/Protein-Serine-Threonine Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Protein-Tyrosine Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-akt,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-bcl-2,
http://linkedlifedata.com/resource/pubmed/chemical/Ptk2 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Trans-Activators,
http://linkedlifedata.com/resource/pubmed/chemical/beta Catenin,
http://linkedlifedata.com/resource/pubmed/chemical/rhoA GTP-Binding Protein
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| pubmed:status |
MEDLINE
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| pubmed:month |
Dec
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| pubmed:issn |
0008-5472
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| pubmed:author | |
| pubmed:issnType |
Print
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| pubmed:day |
1
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| pubmed:volume |
60
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
6750-6
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| pubmed:dateRevised |
2009-11-19
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| pubmed:meshHeading |
pubmed-meshheading:11118062-3T3 Cells,
pubmed-meshheading:11118062-Animals,
pubmed-meshheading:11118062-Apoptosis,
pubmed-meshheading:11118062-Cadherins,
pubmed-meshheading:11118062-Cell Adhesion,
pubmed-meshheading:11118062-Cell Communication,
pubmed-meshheading:11118062-Cell Division,
pubmed-meshheading:11118062-Cell Transformation, Neoplastic,
pubmed-meshheading:11118062-Codon,
pubmed-meshheading:11118062-Cytoskeletal Proteins,
pubmed-meshheading:11118062-Enzyme Activation,
pubmed-meshheading:11118062-Focal Adhesion Kinase 1,
pubmed-meshheading:11118062-Focal Adhesion Protein-Tyrosine Kinases,
pubmed-meshheading:11118062-Gene Expression Regulation, Neoplastic,
pubmed-meshheading:11118062-Genes, ras,
pubmed-meshheading:11118062-MAP Kinase Signaling System,
pubmed-meshheading:11118062-Mice,
pubmed-meshheading:11118062-Phenotype,
pubmed-meshheading:11118062-Point Mutation,
pubmed-meshheading:11118062-Protein-Serine-Threonine Kinases,
pubmed-meshheading:11118062-Protein-Tyrosine Kinases,
pubmed-meshheading:11118062-Proto-Oncogene Proteins,
pubmed-meshheading:11118062-Proto-Oncogene Proteins c-akt,
pubmed-meshheading:11118062-Proto-Oncogene Proteins c-bcl-2,
pubmed-meshheading:11118062-Trans-Activators,
pubmed-meshheading:11118062-Transfection,
pubmed-meshheading:11118062-Transformation, Genetic,
pubmed-meshheading:11118062-beta Catenin,
pubmed-meshheading:11118062-rhoA GTP-Binding Protein
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| pubmed:year |
2000
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| pubmed:articleTitle |
K-ras codon 12 mutation induces higher level of resistance to apoptosis and predisposition to anchorage-independent growth than codon 13 mutation or proto-oncogene overexpression.
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| pubmed:affiliation |
Laboratori d'Investigació Gastrointestinal, Institut de Recerca, Hospital de Sant Pau, Barcelona, Spain.
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| pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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