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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 (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 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 Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 18, 2005 Accepted June 1, 2005 ZAP-70 is a novel conditional heat shock protein 90 (Hsp90)-client protein: 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 Moores UCSD Cancer Center, University of California, San Diego, CA, USA; Chronic Lymphocytic Leukemia Research Consortium (CRC), San Diego, CA, USA Conforma Therapeutics Corporation, San Diego, CA, USA * Corresponding author; email: je-castro{at}ucsd.edu. 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-negative CLL cells expressed non-activated 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-negative 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 upon 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. 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: C. Stuehler, S. Mielke, M. Chatterjee, J. Duell, S. Lurati, F. Rueckert, H. Einsele, R. C. Bargou, and M. S. 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