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rdf:type |
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lifeskim:mentions |
umls-concept:C0007634,
umls-concept:C0021467,
umls-concept:C0021469,
umls-concept:C0023493,
umls-concept:C0038952,
umls-concept:C0086427,
umls-concept:C0282498,
umls-concept:C0332307,
umls-concept:C0439064,
umls-concept:C0542341,
umls-concept:C1514873,
umls-concept:C1546857,
umls-concept:C1548328,
umls-concept:C1553412,
umls-concept:C1556066,
umls-concept:C1619636
|
|
pubmed:issue |
8
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|
pubmed:dateCreated |
2007-3-13
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pubmed:abstractText |
The molecular chaperone Hsp90 is involved in the stabilization and conformational maturation of many signaling proteins that are deregulated in cancers. The geldanamycin derivative 17-AAG is currently tested in clinical trials and known to inhibit the function of Hsp90 and promote the proteasomal degradation of its misfolded client proteins. ATL is a fatal malignancy of T lymphocytes caused by HTLV-I infection and remains incurable. Since Hsp90 is overexpressed in HTLV-I-infected T-cell lines and primary ATL cells, we analyzed the effects of 17-AAG on cell survival, apoptosis and expression of signal transduction proteins. HTLV-I-infected T-cell lines and primary ATL cells were significantly more sensitive to 17-AAG in cell survival assays than normal PBMCs. 17-AAG induced the inhibition of cell cycle and apoptosis. These effects could be mediated by inactivation of NF-kappaB, AP-1 and PI3K/Akt pathways, as well as reduction of expression of proteins involved in the G1-S cell cycle transition and apoptosis. Proteasome inhibition interfered with 17-AAG-mediated signaling proteins depletion. Collectively, our results indicate that 17-AAG suppresses ATL cell survival through, at least in part, destabilization of several client proteins and suggest that 17-AAG is a potentially useful chemotherapeutic agent for ATL.
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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 |
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pubmed:status |
MEDLINE
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pubmed:month |
Apr
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pubmed:issn |
0020-7136
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pubmed:author |
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pubmed:copyrightInfo |
(c) 2007 Wiley-Liss, Inc.
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pubmed:issnType |
Print
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pubmed:day |
15
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pubmed:volume |
120
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
1811-20
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pubmed:dateRevised |
2011-11-4
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pubmed:meshHeading |
pubmed-meshheading:17230513-Adult,
pubmed-meshheading:17230513-Apoptosis,
pubmed-meshheading:17230513-Benzoquinones,
pubmed-meshheading:17230513-Cell Cycle,
pubmed-meshheading:17230513-HSP90 Heat-Shock Proteins,
pubmed-meshheading:17230513-Human T-lymphotropic virus 1,
pubmed-meshheading:17230513-Humans,
pubmed-meshheading:17230513-Lactams, Macrocyclic,
pubmed-meshheading:17230513-Leukemia, T-Cell,
pubmed-meshheading:17230513-Leukemia-Lymphoma, Adult T-Cell,
pubmed-meshheading:17230513-NF-kappa B,
pubmed-meshheading:17230513-Proto-Oncogene Proteins c-akt,
pubmed-meshheading:17230513-Signal Transduction,
pubmed-meshheading:17230513-T-Lymphocytes,
pubmed-meshheading:17230513-Transcription Factor AP-1,
pubmed-meshheading:17230513-Tumor Cells, Cultured
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pubmed:year |
2007
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pubmed:articleTitle |
Inhibition of heat shock protein-90 modulates multiple functions required for survival of human T-cell leukemia virus type I-infected T-cell lines and adult T-cell leukemia cells.
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pubmed:affiliation |
Division of Molecular Virology and Oncology, Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan.
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pubmed:publicationType |
Journal Article,
Retracted Publication,
Research Support, Non-U.S. Gov't
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