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Blood, 1 November 2008, Vol. 112, No. 9, pp. 3827-3834. Prepublished online as a Blood First Edition Paper on August 5, 2008; DOI 10.1182/blood-2008-05-156380. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2008-05-156380v1 112/9/3827    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 Steele, A. J. Articles by Wickremasinghe, R. G. Search for Related Content PubMed PubMed Citation Articles by Steele, A. J. Articles by Wickremasinghe, R. G. Related Collections Neoplasia Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA p53-mediated apoptosis of CLL cells: evidence for a transcription-independent mechanism Andrew J. Steele1, Archibald G. Prentice1, A. Victor Hoffbrand1, Birunthini C. Yogashangary1, Stephen M. Hart1, Elisabeth P. Nacheva1, Julie D. Howard-Reeves1, Veronique M. Duke1, Panagiotis D. Kottaridis1, Kate Cwynarski1, Lyubomir T. Vassilev2, and R. Gitendra Wickremasinghe1 1 Department of Hematology, Royal Free and University College Medical School, London, United Kingdom; and 2 Department of Discovery Oncology, Hoffmann-La Roche, Nutley, NJ The p53 protein plays a key role in securing the apoptotic response of chronic lymphocytic leukemia (CLL) cells to genotoxic agents. Transcriptional induction of proapoptotic proteins including Puma are thought to mediate p53-dependent apoptosis. In contrast, recent studies have identified a novel nontranscriptional mechanism, involving direct binding of p53 to antiapoptotic proteins including Bcl-2 at the mitochondrial surface. Here we show that the major fraction of p53 induced in CLL cells by chlorambucil, fludarabine, or nutlin 3a was stably associated with mitochondria, where it binds to Bcl-2. The Puma protein, which was constitutively expressed in a p53-independent manner, was modestly up-regulated following p53 induction. Pifithrin , an inhibitor of p53-mediated transcription, blocked the up-regulation of Puma and also of p21CIP1. Surprisingly, pifithrin dramatically augmented apoptosis induction by p53-elevating agents and also accelerated the proapoptotic conformation change of the Bax protein. These data suggest that direct interaction of p53 with mitochondrial antiapoptotic proteins including Bcl-2 is the major route for apoptosis induction in CLL cells and that p53's transcriptional targets include proteins that impede this nontranscriptional pathway. Therefore, strategies that block up-regulation of p53-mediated transcription may be of value in enhancing apoptosis induction of CLL cells by p53-elevating drugs. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Suppressing the tumor suppressor in CLL? Chris Pepper Blood 2008 112: 3537-3538. [Full Text] [PDF] This article has been cited by other articles: A. J. Steele, A. G. Prentice, A. V. Hoffbrand, B. C. Yogashangary, S. M. Hart, M. W. Lowdell, E. R. Samuel, J. M. North, E. P. Nacheva, A. Chanalaris, et al. 2-phenylacetylenesulfonamide (PAS) induces p53-independent apoptotic killing of B-chronic lymphocytic leukemia (CLL) cells Blood, August 6, 2009; 114(6): 1217 - 1225. [Abstract] [Full Text] [PDF] P. Secchiero, E. Melloni, M. G. di Iasio, M. Tiribelli, E. Rimondi, F. Corallini, V. Gattei, and G. Zauli Nutlin-3 up-regulates the expression of Notch1 in both myeloid and lymphoid leukemic cells, as part of a negative feedback antiapoptotic mechanism Blood, April 30, 2009; 113(18): 4300 - 4308. [Abstract] [Full Text] [PDF]

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