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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
34
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pubmed:dateCreated |
2000-8-31
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pubmed:abstractText |
Activating mutations of RAS are thought to be early events in the evolution of thyroid follicular neoplasms. We used a doxycycline-inducible expression system to explore the acute effects of H-RAS12 on genomic stability in thyroid PCCL3 cells. At 2-3 days (first or second cell cycle) there was a significant increase in the frequency of micronucleation. Treatment of cells with YVAD-CHO inhibited RAS-induced apoptosis, but had no effect on micronucleation. The effects of H-RAS(V12) were mediated by activation of MAPK, as treatment with PD98059 at concentrations verified to selectively inhibit MEK1 reduced the frequency of prevalence of cells with micronuclei. In addition, doxycycline-inducible expression of a constitutively active MEK1, but not of a mutant RAC1, mimicked the effects of H-RAS(V12). The effects of H-RAS(V12) on genome destabilization were apparent even though the sequence of p53 in PCCL3 cells was confirmed to be wild-type. Acute activation of H-RAS(V12) evoked a proportional increase in both CREST negative and CREST positive micronuclei, indicating that both clastogenic and aneugenic effects were involved. H-RAS(V12) and activated MEK1 also induced centrosome amplification, and chromosome misalignment. Evidence that acute expression of constitutively activated RAS destabilizes the genome of PCCL3 cells is consistent with a mode of tumor initiation in which this oncogene promotes phenotypic progression by predisposing to large scale genomic abnormalities.
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pubmed:grant |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Chromosomal Proteins, Non-Histone,
http://linkedlifedata.com/resource/pubmed/chemical/Doxycycline,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Flavonoids,
http://linkedlifedata.com/resource/pubmed/chemical/MAP Kinase Kinase 1,
http://linkedlifedata.com/resource/pubmed/chemical/Mitogen-Activated Protein Kinase...,
http://linkedlifedata.com/resource/pubmed/chemical/PD 98059,
http://linkedlifedata.com/resource/pubmed/chemical/PTC1 protein, S cerevisiae,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphoprotein Phosphatases,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Phosphatase 2,
http://linkedlifedata.com/resource/pubmed/chemical/Protein-Serine-Threonine Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Saccharomyces cerevisiae Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/centromere protein E,
http://linkedlifedata.com/resource/pubmed/chemical/protein phosphatase 2C,
http://linkedlifedata.com/resource/pubmed/chemical/rac1 GTP-Binding Protein,
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 |
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pubmed:issnType |
Print
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pubmed:day |
10
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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 |
3948-54
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:10951588-Animals,
pubmed-meshheading:10951588-Apoptosis,
pubmed-meshheading:10951588-Cell Nucleus,
pubmed-meshheading:10951588-Chromosomal Proteins, Non-Histone,
pubmed-meshheading:10951588-Doxycycline,
pubmed-meshheading:10951588-Enzyme Inhibitors,
pubmed-meshheading:10951588-Flavonoids,
pubmed-meshheading:10951588-Gamma Rays,
pubmed-meshheading:10951588-Gene Expression Regulation, Neoplastic,
pubmed-meshheading:10951588-MAP Kinase Kinase 1,
pubmed-meshheading:10951588-MAP Kinase Signaling System,
pubmed-meshheading:10951588-Mitogen-Activated Protein Kinase Kinases,
pubmed-meshheading:10951588-Mutation,
pubmed-meshheading:10951588-Phosphoprotein Phosphatases,
pubmed-meshheading:10951588-Protein Phosphatase 2,
pubmed-meshheading:10951588-Protein-Serine-Threonine Kinases,
pubmed-meshheading:10951588-Rats,
pubmed-meshheading:10951588-Saccharomyces cerevisiae Proteins,
pubmed-meshheading:10951588-Thyroid Neoplasms,
pubmed-meshheading:10951588-Tumor Cells, Cultured,
pubmed-meshheading:10951588-rac1 GTP-Binding Protein,
pubmed-meshheading:10951588-ras Proteins
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pubmed:year |
2000
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pubmed:articleTitle |
The RAS oncogene induces genomic instability in thyroid PCCL3 cells via the MAPK pathway.
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pubmed:affiliation |
Division of Endocrinology and Metabolism, University of Cincinnati College of Medicine, Ohio 45267, USA.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.
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