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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.
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Submitted May 16, 2008
Accepted June 24, 2008
p53-mediated apoptosis of CLL cells: evidence for a transcription-independent mechanism
Andrew J Steele, Archibald G Prentice, A Victor Hoffbrand, Birunthini C Yogashangary, Stephen M Hart, Elisabeth P Nacheva, Julie D Howard-Reeves, Veronique M Duke, Panagiotis D Kottaridis, Kate Cwynarski, Lyubomir T Vassilev, and R Gitendra Wickremasinghe*
Department of Hematology, Royal Free and University College Medical School, London, United Kingdom
Department of Discovery Oncology, Roche Research Center, Hoffmann-LaRoche Inc, Nutley, NJ, United States
* Corresponding author; email: r.wickremasinghe{at}medsch.ucl.ac.uk.
The p53 protein plays a key role in securing the apoptotic response of chronic lymphocytic leukaemia (CLL) cells to genotoxic agents. Transcriptional induction of pro-apoptotic proteins including Puma are thought to mediate p53-dependent apoptosis. In contrast, recent studies have identified a novel non-transcriptional mechanism, involving direct binding of p53 to anti-apoptotic 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 upregulated following p53 induction. Pifithrin  , an inhibitor of p53-mediated transcription, blocked this upregulation of Puma and also of p21CIP1 . Surprisingly, pifithrin dramatically augmented apoptosis induction by p53-elevating agents and also accelerated the pro-apoptotic conformation change of the Bax protein. These data suggest that direct interaction of p53 with mitochondrial anti-apoptotic proteins including Bcl-2 is the major route for apoptosis induction in CLL cells and that p53's transcriptional targets include proteins which impede this non-transcriptional pathway. Therefore, strategies which block upregulation of p53-mediated transcription may be of value in enhancing apoptosis induction of CLL cells by p53-elevating drugs.
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