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Blood, 1 October 2005, Vol. 106, No. 7, pp. 2506-2512. Prepublished online as a Blood First Edition Paper on June 21, 2005; DOI 10.1182/blood-2005-03-1099. This Article Full Text Full Text (PDF) All Versions of this Article: 2005-03-1099v1 106/7/2506    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Castro, J. E. Articles by Kipps, T. J. Search for Related Content PubMed PubMed Citation Articles by Castro, J. E. Articles by Kipps, T. J. Related Collections Apoptosis Signal Transduction Free Research Articles Neoplasia Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA ZAP-70 is a novel conditional heat shock protein 90 (Hsp90) client: inhibition of Hsp90 leads to ZAP-70 degradation, apoptosis, and impaired signaling in chronic lymphocytic leukemia Januario E. Castro, Carlos E. Prada, Olivier Loria, Adeela Kamal, Liguang Chen, Francis J. Burrows, and Thomas J. Kipps From the Moores University of California San Diego (UCSD) Cancer Center, University of California; the Conforma Therapeutics Corporation; and the Chronic Lymphocytic Leukemia Research Consortium (CRC), San Diego, CA. The zeta-associated protein of 70 kDa (ZAP-70) is expressed in patients with aggressive chronic lymphocytic leukemia (CLL). We found that ZAP-70+ CLL cells expressed activated heat-shock protein 90 (Hsp90) with high binding affinity for Hsp90 inhibitors, such as 17-allyl-amino-demethoxy-geldanamycin (17-AAG), whereas normal lymphocytes or ZAP-70- CLL cells expressed nonactivated Hsp90. Activated Hsp90 bound and stabilized ZAP-70, which behaved like an Hsp90 client protein only in CLL cells. Treatment with Hsp90 inhibitors such as 17-AAG and 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) induced ZAP-70 degradation and apoptosis in CLL cells but not in T cells, and also impaired B-cell receptor signaling in leukemia cells. Transduction of ZAP-70- CLL cells with an adenovirus encoding ZAP-70 activated Hsp90 and specifically rendered the leukemia cells sensitive to 17-AAG. These data indicate that Hsp90 is necessary for ZAP-70 expression and activity; that ZAP-70 is unique among Hsp90 clients, in that its chaperone-dependency is conditional on the cell type in which it is expressed; and also that ZAP-70 is required for cell survival and signaling in CLL. Additionally, ZAP-70 expression in CLL cells confers markedly heightened sensitivity to 17-AAG or 17-DMAG, suggesting that these or other Hsp90 inhibitors could be valuable therapeutically in patients with aggressive CLL. (Blood. 2005;106:2506-2512) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Fighting CLL cells: deciphering the enemy Emili Montserrat Blood 2005 106: 2226. [Full Text] [PDF] This article has been cited by other articles: A. K. Mandal, N. B. Nillegoda, J. A. Chen, and A. J. Caplan Ydj1 Protects Nascent Protein Kinases from Degradation and Controls the Rate of Their Maturation Mol. Cell. 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Eldering Differential Noxa/Mcl-1 balance in peripheral versus lymph node chronic lymphocytic leukemia cells correlates with survival capacity Blood, February 15, 2007; 109(4): 1660 - 1668. [Abstract] [Full Text] [PDF] T. D. Shanafelt, J. C. Byrd, T. G. Call, C. S. Zent, and N. E. Kay Narrative review: initial management of newly diagnosed, early-stage chronic lymphocytic leukemia. Ann Intern Med, September 19, 2006; 145(6): 435 - 447. [Abstract] [Full Text] [PDF]

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