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rdf:type |
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lifeskim:mentions |
umls-concept:C0014597,
umls-concept:C0033684,
umls-concept:C0127400,
umls-concept:C0871261,
umls-concept:C1335191,
umls-concept:C1517945,
umls-concept:C1704632,
umls-concept:C1706817,
umls-concept:C1709385,
umls-concept:C2611812,
umls-concept:C2613365,
umls-concept:C2911692
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pubmed:issue |
24
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pubmed:dateCreated |
2005-6-13
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pubmed:abstractText |
The apoptosis-promoting protein Par-4 has been shown to be down-regulated in Ras-transformed NIH 3T3 fibroblasts through the Raf/MEK/ERK MAPK pathway. Because mutations of the ras gene are most often found in tumors of epithelial origin, we explored the signaling pathways utilized by oncogenic Ras to down-regulate Par-4 in RIE-1 and rat ovarian surface epithelial (ROSE) cells. We determined that constitutive activation of the Raf, phosphatidylinositol 3-kinase, or Ral guanine nucleotide exchange factor effector pathway alone was not sufficient to down-regulate Par-4 in RIE-1 or ROSE cells. However, treatment of Ras-transformed RIE-1 or ROSE cells with the MEK inhibitors U0126 and PD98059 increased Par-4 protein expression. Thus, although oncogenic Ras utilizes the Raf/MEK/ERK pathway to down-regulate Par-4 in both fibroblasts and epithelial cells, Ras activation of an additional signaling pathway(s) is required to achieve the same outcome in epithelial cells. Methylation-specific PCR showed that the par-4 promoter is methylated in Ras-transformed cells through a MEK-dependent pathway and that treatment with the DNA methyltransferase inhibitor azadeoxycytidine restored Par-4 mRNA transcript and protein levels, suggesting that the mechanism for Ras-mediated down-regulation of Par-4 is by promoter methylation. Support for this possibility is provided by our observation that Ras transformation was associated with up-regulation of Dnmt1 and Dnmt3 DNA methyltransferase expression. Finally, ectopic Par-4 expression significantly reduced Ras-mediated growth in soft agar, but not morphological transformation, highlighting the importance of Par-4 down-regulation in specific aspects of Ras-mediated transformation of epithelial cells.
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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/Agar,
http://linkedlifedata.com/resource/pubmed/chemical/Apoptosis Regulatory Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Azacitidine,
http://linkedlifedata.com/resource/pubmed/chemical/Butadienes,
http://linkedlifedata.com/resource/pubmed/chemical/DNA, Complementary,
http://linkedlifedata.com/resource/pubmed/chemical/DNA (Cytosine-5-)-Methyltransferase,
http://linkedlifedata.com/resource/pubmed/chemical/DNA...,
http://linkedlifedata.com/resource/pubmed/chemical/DNA methyltransferase 3A,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Flavonoids,
http://linkedlifedata.com/resource/pubmed/chemical/Intracellular Signaling Peptides...,
http://linkedlifedata.com/resource/pubmed/chemical/Nitriles,
http://linkedlifedata.com/resource/pubmed/chemical/PD 98059,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphatidylinositol 3-Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/RNA,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Messenger,
http://linkedlifedata.com/resource/pubmed/chemical/U 0126,
http://linkedlifedata.com/resource/pubmed/chemical/decitabine,
http://linkedlifedata.com/resource/pubmed/chemical/prostate apoptosis response-4...,
http://linkedlifedata.com/resource/pubmed/chemical/raf Kinases
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pubmed:status |
MEDLINE
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pubmed:month |
Jun
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pubmed:issn |
0021-9258
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
17
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pubmed:volume |
280
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
23363-70
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pubmed:dateRevised |
2010-11-18
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pubmed:meshHeading |
pubmed-meshheading:15831492-Agar,
pubmed-meshheading:15831492-Alleles,
pubmed-meshheading:15831492-Animals,
pubmed-meshheading:15831492-Apoptosis,
pubmed-meshheading:15831492-Apoptosis Regulatory Proteins,
pubmed-meshheading:15831492-Azacitidine,
pubmed-meshheading:15831492-Blotting, Northern,
pubmed-meshheading:15831492-Blotting, Western,
pubmed-meshheading:15831492-Butadienes,
pubmed-meshheading:15831492-Cell Line,
pubmed-meshheading:15831492-Cell Line, Tumor,
pubmed-meshheading:15831492-Cell Transformation, Neoplastic,
pubmed-meshheading:15831492-DNA, Complementary,
pubmed-meshheading:15831492-DNA (Cytosine-5-)-Methyltransferase,
pubmed-meshheading:15831492-DNA Methylation,
pubmed-meshheading:15831492-Down-Regulation,
pubmed-meshheading:15831492-Enzyme Inhibitors,
pubmed-meshheading:15831492-Epithelial Cells,
pubmed-meshheading:15831492-Female,
pubmed-meshheading:15831492-Fibroblasts,
pubmed-meshheading:15831492-Flavonoids,
pubmed-meshheading:15831492-Genetic Vectors,
pubmed-meshheading:15831492-Humans,
pubmed-meshheading:15831492-Intracellular Signaling Peptides and Proteins,
pubmed-meshheading:15831492-Mice,
pubmed-meshheading:15831492-Mutation,
pubmed-meshheading:15831492-NIH 3T3 Cells,
pubmed-meshheading:15831492-Nitriles,
pubmed-meshheading:15831492-Ovary,
pubmed-meshheading:15831492-Phosphatidylinositol 3-Kinases,
pubmed-meshheading:15831492-Polymerase Chain Reaction,
pubmed-meshheading:15831492-RNA,
pubmed-meshheading:15831492-RNA, Messenger,
pubmed-meshheading:15831492-Rats,
pubmed-meshheading:15831492-Signal Transduction,
pubmed-meshheading:15831492-Up-Regulation,
pubmed-meshheading:15831492-raf Kinases
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pubmed:year |
2005
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pubmed:articleTitle |
Ras-mediated loss of the pro-apoptotic response protein Par-4 is mediated by DNA hypermethylation through Raf-independent and Raf-dependent signaling cascades in epithelial cells.
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pubmed:affiliation |
Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, 27599-7295, USA.
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pubmed:publicationType |
Journal Article
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