| pubmed-article:17353907 | rdf:type | pubmed:Citation | lld:pubmed |
| pubmed-article:17353907 | lifeskim:mentions | umls-concept:C0033681 | lld:lifeskim |
| pubmed-article:17353907 | lifeskim:mentions | umls-concept:C1334894 | lld:lifeskim |
| pubmed-article:17353907 | lifeskim:mentions | umls-concept:C1332080 | lld:lifeskim |
| pubmed-article:17353907 | lifeskim:mentions | umls-concept:C1515673 | lld:lifeskim |
| pubmed-article:17353907 | lifeskim:mentions | umls-concept:C0205263 | lld:lifeskim |
| pubmed-article:17353907 | lifeskim:mentions | umls-concept:C1879547 | lld:lifeskim |
| pubmed-article:17353907 | pubmed:issue | 38 | lld:pubmed |
| pubmed-article:17353907 | pubmed:dateCreated | 2007-8-16 | lld:pubmed |
| pubmed-article:17353907 | 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. | lld:pubmed |
| pubmed-article:17353907 | pubmed:grant | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:17353907 | pubmed:grant | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:17353907 | pubmed:commentsCorrections | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:17353907 | pubmed:language | eng | lld:pubmed |
| pubmed-article:17353907 | pubmed:journal | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:17353907 | pubmed:citationSubset | IM | lld:pubmed |
| pubmed-article:17353907 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:17353907 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:17353907 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:17353907 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:17353907 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:17353907 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:17353907 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:17353907 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:17353907 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:17353907 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:17353907 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:17353907 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:17353907 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:17353907 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:17353907 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:17353907 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:17353907 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:17353907 | pubmed:status | MEDLINE | lld:pubmed |
| pubmed-article:17353907 | pubmed:month | Aug | lld:pubmed |
| pubmed-article:17353907 | pubmed:issn | 0950-9232 | lld:pubmed |
| pubmed-article:17353907 | pubmed:author | pubmed-author:LimPP | lld:pubmed |
| pubmed-article:17353907 | pubmed:author | pubmed-author:WasikM AMA | lld:pubmed |
| pubmed-article:17353907 | pubmed:author | pubmed-author:MarzecMM | lld:pubmed |
| pubmed-article:17353907 | pubmed:author | pubmed-author:BucksDD | lld:pubmed |
| pubmed-article:17353907 | pubmed:author | pubmed-author:RaghunathP... | lld:pubmed |
| pubmed-article:17353907 | pubmed:author | pubmed-author:WlodarskaHH | lld:pubmed |
| pubmed-article:17353907 | pubmed:author | pubmed-author:KasprzyckaMM | lld:pubmed |
| pubmed-article:17353907 | pubmed:author | pubmed-author:HalariRR | lld:pubmed |
| pubmed-article:17353907 | pubmed:author | pubmed-author:El-SalemMM | lld:pubmed |
| pubmed-article:17353907 | pubmed:issnType | Print | lld:pubmed |
| pubmed-article:17353907 | pubmed:day | 16 | lld:pubmed |
| pubmed-article:17353907 | pubmed:volume | 26 | lld:pubmed |
| pubmed-article:17353907 | pubmed:owner | NLM | lld:pubmed |
| pubmed-article:17353907 | pubmed:authorsComplete | Y | lld:pubmed |
| pubmed-article:17353907 | pubmed:pagination | 5606-14 | lld:pubmed |
| pubmed-article:17353907 | pubmed:dateRevised | 2011-11-17 | lld:pubmed |
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| pubmed-article:17353907 | pubmed:year | 2007 | lld:pubmed |
| pubmed-article:17353907 | pubmed:articleTitle | Oncogenic tyrosine kinase NPM/ALK induces activation of the rapamycin-sensitive mTOR signaling pathway. | lld:pubmed |
| pubmed-article:17353907 | pubmed:affiliation | Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104-4283, USA. | lld:pubmed |
| pubmed-article:17353907 | pubmed:publicationType | Journal Article | lld:pubmed |
| pubmed-article:17353907 | pubmed:publicationType | Research Support, N.I.H., Extramural | lld:pubmed |
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