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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
22
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pubmed:dateCreated |
2010-11-26
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pubmed:abstractText |
The aberrant overexpression of Wilms tumor 1 (WT1) in myeloid leukemia plays an important role in blast cell survival and resistance to chemotherapy. High expression of WT1 is also associated with relapse and shortened disease-free survival in patients. However, the mechanisms by which WT1 expression is regulated in leukemia remain unclear. Here, we report that heat shock protein 90 (Hsp90), which plays a critical role in the folding and maturation of several oncogenic proteins, associates with WT1 protein and stabilizes its expression. Pharmacologic inhibition of Hsp90 resulted in ubiquitination and subsequent proteasome-dependant degradation of WT1. RNAi-mediated silencing of WT1 reduced the survival of leukemia cells and increased the sensitivity of these cells to chemotherapy and Hsp90 inhibition. Furthermore, Hsp90 inhibitors 17-AAG [17-(allylamino)-17-demethoxygeldanamycin] and STA-9090 significantly reduced the growth of myeloid leukemia xenografts in vivo and effectively down-regulated the expression of WT1 and its downstream target proteins, c-Myc and Bcl-2. Collectively, our studies identify WT1 as a novel Hsp90 client and support the crucial role for the WT1-Hsp90 interaction in maintaining leukemia cell survival. These findings have significant implications for developing effective therapies for myeloid leukemias and offer a strategy to inhibit the oncogenic functions of WT1 by clinically available Hsp90 inhibitors.
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pubmed:grant |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
AIM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/17-(allylamino)-17-demethoxygeldanam...,
http://linkedlifedata.com/resource/pubmed/chemical/Antineoplastic Agents, Phytogenic,
http://linkedlifedata.com/resource/pubmed/chemical/Benzoquinones,
http://linkedlifedata.com/resource/pubmed/chemical/Etoposide,
http://linkedlifedata.com/resource/pubmed/chemical/HSP90 Heat-Shock Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Lactams, Macrocyclic,
http://linkedlifedata.com/resource/pubmed/chemical/Proteasome Endopeptidase Complex,
http://linkedlifedata.com/resource/pubmed/chemical/STA 9090,
http://linkedlifedata.com/resource/pubmed/chemical/Triazoles,
http://linkedlifedata.com/resource/pubmed/chemical/WT1 Proteins
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pubmed:status |
MEDLINE
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pubmed:month |
Nov
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pubmed:issn |
1528-0020
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pubmed:author |
pubmed-author:BaerMaria RMR,
pubmed-author:BansalHimaH,
pubmed-author:BansalSanjayS,
pubmed-author:BarsoumJamesJ,
pubmed-author:BattiwallaMinooM,
pubmed-author:BlackmanRonald KRK,
pubmed-author:FoleyKevin PKP,
pubmed-author:GilesFrancis JFJ,
pubmed-author:KellyKevinK,
pubmed-author:LeeKelvin PKP,
pubmed-author:PadmanabhanSwaminathanS,
pubmed-author:ProiaDavid ADA,
pubmed-author:RaoManjeetM,
pubmed-author:SangJimJ,
pubmed-author:SwordsRonanR,
pubmed-author:TomlinsonGail EGE,
pubmed-author:YingWeiwenW
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pubmed:issnType |
Electronic
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pubmed:day |
25
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pubmed:volume |
116
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
4591-9
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pubmed:meshHeading |
pubmed-meshheading:20651072-Animals,
pubmed-meshheading:20651072-Antineoplastic Agents, Phytogenic,
pubmed-meshheading:20651072-Apoptosis,
pubmed-meshheading:20651072-Benzoquinones,
pubmed-meshheading:20651072-Cell Line, Tumor,
pubmed-meshheading:20651072-Etoposide,
pubmed-meshheading:20651072-Female,
pubmed-meshheading:20651072-Gene Expression Regulation, Leukemic,
pubmed-meshheading:20651072-Gene Silencing,
pubmed-meshheading:20651072-HSP90 Heat-Shock Proteins,
pubmed-meshheading:20651072-Humans,
pubmed-meshheading:20651072-Lactams, Macrocyclic,
pubmed-meshheading:20651072-Leukemia, Myeloid,
pubmed-meshheading:20651072-Mice,
pubmed-meshheading:20651072-Mice, SCID,
pubmed-meshheading:20651072-Proteasome Endopeptidase Complex,
pubmed-meshheading:20651072-Protein Interaction Domains and Motifs,
pubmed-meshheading:20651072-Protein Structure, Tertiary,
pubmed-meshheading:20651072-Triazoles,
pubmed-meshheading:20651072-WT1 Proteins
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pubmed:year |
2010
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pubmed:articleTitle |
Heat shock protein 90 regulates the expression of Wilms tumor 1 protein in myeloid leukemias.
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pubmed:affiliation |
Cancer Therapy and Research Center at The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA. bansals@uthscsa.edu
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
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