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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
38
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pubmed:dateCreated |
2007-8-16
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pubmed:abstractText |
The mechanisms of cell transformation mediated by the nucleophosmin (NPM)/anaplastic lymphoma kinase (ALK) tyrosine kinase are only partially understood. Here, we report that cell lines and native tissues derived from the NPM/ALK-expressing T-cell lymphoma display persistent activation of mammalian target of rapamycin (mTOR) as determined by phosphorylation of mTOR targets S6rp and 4E-binding protein 1 (4E-BP1). The mTOR activation is serum growth factor-independent but nutrient-dependent. It is also dependent on the expression and enzymatic activity of NPM/ALK as demonstrated by cell transfection with wild-type and functionally deficient NPM/ALK, small interfering RNA (siRNA)-mediated NPM/ALK depletion and kinase activity suppression using the inhibitor WHI-P154. The NPM/ALK-induced mTOR activation is transduced through the mitogen-induced extracellular kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathway and, to a much lesser degree, through the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway. Accordingly, whereas the low-dose PI3K inhibitor wortmannin and Akt inhibitor III profoundly inhibited Akt phosphorylation, they had a very modest effect on S6rp and 4E-BP1 phosphorylation. In turn, MEK inhibitors U0126 and PD98059 and siRNA-mediated depletion of either ERK1 or ERK2 inhibited S6rp phosphorylation much more effectively. Finally, the mTOR inhibitor rapamycin markedly decreased proliferation and increased the apoptotic rate of ALK+TCL cells. These findings identify mTOR as a novel key target of NPM/ALK and suggest that mTOR inhibitors may prove effective in therapy of ALK-induced malignancies.
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pubmed:grant |
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pubmed:commentsCorrections |
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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/Extracellular Signal-Regulated MAP...,
http://linkedlifedata.com/resource/pubmed/chemical/MTOR protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Mitogen-Activated Protein Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Nuclear Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphatidylinositol 3-Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Kinase Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Protein-Tyrosine Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-akt,
http://linkedlifedata.com/resource/pubmed/chemical/Quinazolines,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Small Interfering,
http://linkedlifedata.com/resource/pubmed/chemical/Receptor Protein-Tyrosine Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Sirolimus,
http://linkedlifedata.com/resource/pubmed/chemical/TOR Serine-Threonine Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/WHI P154,
http://linkedlifedata.com/resource/pubmed/chemical/anaplastic lymphoma kinase,
http://linkedlifedata.com/resource/pubmed/chemical/nucleophosmin
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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 |
16
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pubmed:volume |
26
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
5606-14
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pubmed:dateRevised |
2011-11-17
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pubmed:meshHeading |
pubmed-meshheading:17353907-Animals,
pubmed-meshheading:17353907-Blotting, Western,
pubmed-meshheading:17353907-Cell Line,
pubmed-meshheading:17353907-Cell Line, Tumor,
pubmed-meshheading:17353907-Cell Proliferation,
pubmed-meshheading:17353907-Cell Survival,
pubmed-meshheading:17353907-Extracellular Signal-Regulated MAP Kinases,
pubmed-meshheading:17353907-Humans,
pubmed-meshheading:17353907-Immunohistochemistry,
pubmed-meshheading:17353907-Lymphoma, T-Cell,
pubmed-meshheading:17353907-Mitogen-Activated Protein Kinases,
pubmed-meshheading:17353907-Models, Biological,
pubmed-meshheading:17353907-Nuclear Proteins,
pubmed-meshheading:17353907-Phosphatidylinositol 3-Kinases,
pubmed-meshheading:17353907-Protein Kinase Inhibitors,
pubmed-meshheading:17353907-Protein Kinases,
pubmed-meshheading:17353907-Protein-Tyrosine Kinases,
pubmed-meshheading:17353907-Proto-Oncogene Proteins c-akt,
pubmed-meshheading:17353907-Quinazolines,
pubmed-meshheading:17353907-RNA, Small Interfering,
pubmed-meshheading:17353907-Receptor Protein-Tyrosine Kinases,
pubmed-meshheading:17353907-Signal Transduction,
pubmed-meshheading:17353907-Sirolimus,
pubmed-meshheading:17353907-TOR Serine-Threonine Kinases,
pubmed-meshheading:17353907-Transfection
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pubmed:year |
2007
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pubmed:articleTitle |
Oncogenic tyrosine kinase NPM/ALK induces activation of the rapamycin-sensitive mTOR signaling pathway.
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pubmed:affiliation |
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104-4283, USA.
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pubmed:publicationType |
Journal Article,
Research Support, N.I.H., Extramural
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