Source:http://linkedlifedata.com/resource/pubmed/id/17900262
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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
12
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pubmed:dateCreated |
2007-10-25
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pubmed:abstractText |
FKHRL1 (also called FOXO3a) is a member of the Forkhead Box, class O (FOXO) subfamily of forkhead transcription factors and functions downstream of Bcr-Abl tyrosine kinase as a phosphorylated inactive form in chronic myelogenous leukemia (CML). The Bcr-Abl tyrosine kinase inhibitor imatinib induces cell cycle arrest and subsequent apoptosis via the conversion of FKHRL1 from the phosphorylated inactive form to the dephosphorylated active form in CML-derived cell lines. In the present study, we examined whether active FKHRL1 can overcome resistance to imatinib. To this end, we generated a 4-hydroxytamoxifen-inducible active FKHRL1 (FKHRL1-TM; a triple mutant of FKHRL1 in which all three Akt phosphorylation sites have been mutated)-estrogen receptor fusion protein expression system in CML-derived imatinib-resistant cell lines. 4-Hydroxytamoxifen inhibited cell growth and cell cycle progression, and subsequently induced apoptosis, accompanied by upregulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Thus, active FKHRL1 antagonized deregulated proliferation and induced apoptosis in these cell lines. In addition, imatinib-resistant cells underwent apoptosis after transfection with full-length TRAIL cDNA. Collectively, our results suggest that active FKHRL1 can overcome imatinib resistance in CML cells, in part via TRAIL production.
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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/Antineoplastic Agents,
http://linkedlifedata.com/resource/pubmed/chemical/FOXO3 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Forkhead Transcription Factors,
http://linkedlifedata.com/resource/pubmed/chemical/Piperazines,
http://linkedlifedata.com/resource/pubmed/chemical/Pyrimidines,
http://linkedlifedata.com/resource/pubmed/chemical/TNF-Related Apoptosis-Inducing...,
http://linkedlifedata.com/resource/pubmed/chemical/TNFSF10 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/imatinib
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pubmed:status |
MEDLINE
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pubmed:month |
Dec
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pubmed:issn |
1349-7006
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pubmed:author | |
pubmed:issnType |
Electronic
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pubmed:volume |
98
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
1949-58
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pubmed:meshHeading |
pubmed-meshheading:17900262-Animals,
pubmed-meshheading:17900262-Antineoplastic Agents,
pubmed-meshheading:17900262-Apoptosis,
pubmed-meshheading:17900262-Cell Cycle,
pubmed-meshheading:17900262-Cell Division,
pubmed-meshheading:17900262-Cell Line, Tumor,
pubmed-meshheading:17900262-Drug Resistance, Neoplasm,
pubmed-meshheading:17900262-Forkhead Transcription Factors,
pubmed-meshheading:17900262-Humans,
pubmed-meshheading:17900262-K562 Cells,
pubmed-meshheading:17900262-Leukemia, Myelogenous, Chronic, BCR-ABL Positive,
pubmed-meshheading:17900262-Piperazines,
pubmed-meshheading:17900262-Polymerase Chain Reaction,
pubmed-meshheading:17900262-Pyrimidines,
pubmed-meshheading:17900262-TNF-Related Apoptosis-Inducing Ligand,
pubmed-meshheading:17900262-Transfection
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pubmed:year |
2007
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pubmed:articleTitle |
Active FKHRL1 overcomes imatinib resistance in chronic myelogenous leukemia-derived cell lines via the production of tumor necrosis factor-related apoptosis-inducing ligand.
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pubmed:affiliation |
Division of Hematology, Department of Medicine, Jichi Medical University, Tochigi-ken 329-0498, Japan.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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