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Blood, 1 December 2008, Vol. 112, No. 12, pp. 4665-4674. Prepublished online as a Blood First Edition Paper on September 2, 2008; DOI 10.1182/blood-2008-02-139139. This Article Full Text (PDF) All Versions of this Article: blood-2008-02-139139v1 112/12/4665    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 Trentin, L. Articles by Brunati, A. M. Search for Related Content PubMed PubMed Citation Articles by Trentin, L. Articles by Brunati, A. M. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted February 14, 2008 Accepted July 3, 2008 Geldanamycin-induced Lyn dissociation from aberrant HSP90-stabilized cytosolic complex is an early event in apoptotic mechanisms in B-chronic lymphocytic leukemia Livio Trentin, Martina Frasson, Arianna Donella-Deana, Federica Frezzato, Mario A. Pagano, Elena Tibaldi, Cristina Gattazzo, Renato Zambello, Gianpietro Semenzato*, and Anna M. Brunati Department of Clinical and Experimental Medicine, Hematology and Clinical Immunology Branch, Padua University School of Medicine, Padua, Italy Department of Biological Chemistry, University of Padua, Padua, Italy Centro di Eccellenza per la Ricerca, Venetian Institute for Molecular Medicine (VIMM), Italy * Corresponding author; email: g.semenzato{at}unipd.it. Lyn, a tyrosine kinase belonging to the Src family, plays a key role as a switch molecule that couples the B cell receptor to downstream signalling. In B-CLL cells, Lyn is over-expressed, anomalously present in the cytosol and displays a high constitutive activity, as compared to normal B lymphocytes. The aim of this work was to gain insights into the molecular mechanisms underlying these aberrant properties of Lyn, which have already been demonstrated to be related to defective apoptosis in B-CLL cells. Herein, Lyn is described to be in an active conformation as integral component of an aberrant cytosolic 600 kDa multiprotein complex in B-CLL cells, associated with several proteins, such as Hsp90 through its catalytic domain, and HS1 and SHP-1L through its SH3 domain. In particular, Hsp90 appears tightly bound to cytosolic Lyn (CL), thus stabilizing the aberrant complex and converting individual transient interactions into stable ones. We also demonstrate that treatment of B-CLL cells with geldanamycin, an Hsp90 inhibitor already reported to induce cell death, is capable of dissociating the CL complex in the early phases of apoptosis and thus inactivating CL itself. These data identify the CL complex as a potential target for therapy in B-CLL. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: Enhanced Fas-associated death domain recruitment by histone deacetylase inhibitors is critical for the sensitization of chronic lymphocytic leukemia cells to TRAIL-induced apoptosis Mol. Cancer Ther., November 1, 2009; 8(11): 3088 - 3097.

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