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rdf:type |
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lifeskim:mentions |
umls-concept:C0031686,
umls-concept:C0040005,
umls-concept:C0079904,
umls-concept:C0086982,
umls-concept:C0109317,
umls-concept:C0301625,
umls-concept:C0752312,
umls-concept:C0752313,
umls-concept:C1150579,
umls-concept:C1158884,
umls-concept:C1333340,
umls-concept:C1366882,
umls-concept:C1370600,
umls-concept:C1420556,
umls-concept:C1424530,
umls-concept:C1523116,
umls-concept:C1705767,
umls-concept:C1705791,
umls-concept:C2349975
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pubmed:issue |
25
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pubmed:dateCreated |
2004-6-14
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pubmed:abstractText |
We previously reported that suppression of the MEK/ERK pathway increases drug resistance of SiHa cells. In this study, we further characterized the underlying mechanism of this phenomenon. Pretreatment of SiHa cells with MEK/ERK inhibitor enhanced cisplatin-induced NF-kappaB activation. However, results of immunoblotting analysis showed that neither cisplatin nor MEK/ERK inhibitors induced marked IkappaBalpha degradation, suggesting that suppression of the MEK/ERK signaling pathway may enhance cisplatin-induced NF-kappaB activation via mechanisms other than the conventional pathway. Previous findings that protein phosphatase 4 (PP4), a nuclear serine/threonine phosphatase, directly interacts with and activates NF-kappaB led us to examine the phosphorylation status of NF-kappaB p65. Coincident with activation of NF-kappaB, cisplatin induced Ser phosphorylation but decreased Thr phosphorylation of NF-kappaB p65. Suppression of the MEK/ERK pathway further enhanced cisplatin-induced Thr dephosphorylation but did not affect cisplatin-induced Ser phosphorylation of NF-kappaB p65. Further, in parallel with Thr dephosphorylation, the protein level of nuclear PP4 was increased in cisplatin-treated cells and was further increased by suppression of the MEK/ERK pathway. SiHa cells were then transfected by a sense or an antisense PP4 gene. PP4-overexpressing cells showed a decrease in Thr phosphorylation of NF-kappaB p65 to nearly undetectable levels, and both basal and cisplatin-induced NF-kappaB activities were higher than those in parental cells. By contrast, cisplatin, either alone or with MEK/ERK inhibitors, induced little NF-kappaB activation in antisense PP4-transfected cells. Coprecipitated complex kinase assay revealed a fragment of NF-kappaB p65 (amino acids 279-444) to contain potential phosphorylation sites that directly interact with PP4. Further studies by site-directed mutagenesis suggested that Thr(435) was the major phosphorylation site.
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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/Antineoplastic Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Cisplatin,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Flavonoids,
http://linkedlifedata.com/resource/pubmed/chemical/Mitogen-Activated Protein Kinase 1,
http://linkedlifedata.com/resource/pubmed/chemical/Mitogen-Activated Protein Kinase...,
http://linkedlifedata.com/resource/pubmed/chemical/Mitogen-Activated Protein Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/NF-kappa B,
http://linkedlifedata.com/resource/pubmed/chemical/PD 98059,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphoprotein Phosphatases,
http://linkedlifedata.com/resource/pubmed/chemical/Serine,
http://linkedlifedata.com/resource/pubmed/chemical/Threonine,
http://linkedlifedata.com/resource/pubmed/chemical/Transcription Factor RelA,
http://linkedlifedata.com/resource/pubmed/chemical/protein phosphatase 4
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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 |
18
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pubmed:volume |
279
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
26143-8
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:15073167-Antineoplastic Agents,
pubmed-meshheading:15073167-Cell Line,
pubmed-meshheading:15073167-Cell Line, Tumor,
pubmed-meshheading:15073167-Cell Nucleus,
pubmed-meshheading:15073167-Cisplatin,
pubmed-meshheading:15073167-Enzyme Activation,
pubmed-meshheading:15073167-Enzyme Inhibitors,
pubmed-meshheading:15073167-Escherichia coli,
pubmed-meshheading:15073167-Flavonoids,
pubmed-meshheading:15073167-Humans,
pubmed-meshheading:15073167-Immunoblotting,
pubmed-meshheading:15073167-Mitogen-Activated Protein Kinase 1,
pubmed-meshheading:15073167-Mitogen-Activated Protein Kinase Kinases,
pubmed-meshheading:15073167-Mitogen-Activated Protein Kinases,
pubmed-meshheading:15073167-Mutagenesis, Site-Directed,
pubmed-meshheading:15073167-NF-kappa B,
pubmed-meshheading:15073167-Phosphoprotein Phosphatases,
pubmed-meshheading:15073167-Phosphorylation,
pubmed-meshheading:15073167-Plasmids,
pubmed-meshheading:15073167-Precipitin Tests,
pubmed-meshheading:15073167-Protein Binding,
pubmed-meshheading:15073167-Serine,
pubmed-meshheading:15073167-Signal Transduction,
pubmed-meshheading:15073167-Threonine,
pubmed-meshheading:15073167-Transcription Factor RelA,
pubmed-meshheading:15073167-Transfection
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pubmed:year |
2004
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pubmed:articleTitle |
Suppression of MEK/ERK signaling pathway enhances cisplatin-induced NF-kappaB activation by protein phosphatase 4-mediated NF-kappaB p65 Thr dephosphorylation.
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pubmed:affiliation |
Cancer Research Center, College of Medicine, National Taiwan University, Republic of China.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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