p53-mediated apoptosis of CLL cells: evidence for a transcription-independent mechanism
p53-mediated apoptosis of CLL cells: evidence for a transcription-independent mechanism
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 alpha, an inhibitor of p53-mediated transcription, blocked the up-regulation of Puma and also of p21(CIP1). Surprisingly, pifithrin alpha 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.
3827-3834
Steele, Andrew J.
4349f6aa-2e3a-49a8-be73-7716056ae089
Prentice, Archibald G.
a834a471-b816-4c3a-a3d4-70fa8dd2c982
Hoffbrand, A. Victor
f33e01e3-5c17-40fd-b66d-155e4f3bbffe
Yogashangary, Birunthini C.
309cbe4c-8d44-43e7-b744-453c4acd3d29
Hart, Stephen M.
43396380-899f-44e0-86c3-3aa10aae993c
Nacheva, Elisabeth P.
3052e0f3-bd51-463e-a4e0-5e69513e6ab2
Howard-Reeves, Julie D.
d5726d5e-a628-4c71-bfdd-bd6887d5fb0e
Duke, Veronique M.
d23d86f3-a0ed-42d9-8953-4bd15a333c41
Kottaridis, Panagiotis D.
b83d9bdd-30b7-42c7-afea-ef0d1947fad2
Cwynarski, Kate
34d6aef4-8106-40ee-9609-b44460ccb971
Vassilev, Lyubomir T.
d09777df-25ab-45c1-a9bb-bcdbd0b262ed
Wickremasinghe, R. Gitendra.
9c9c14d3-3ec8-401a-949b-5222c626b165
1 November 2008
Steele, Andrew J.
4349f6aa-2e3a-49a8-be73-7716056ae089
Prentice, Archibald G.
a834a471-b816-4c3a-a3d4-70fa8dd2c982
Hoffbrand, A. Victor
f33e01e3-5c17-40fd-b66d-155e4f3bbffe
Yogashangary, Birunthini C.
309cbe4c-8d44-43e7-b744-453c4acd3d29
Hart, Stephen M.
43396380-899f-44e0-86c3-3aa10aae993c
Nacheva, Elisabeth P.
3052e0f3-bd51-463e-a4e0-5e69513e6ab2
Howard-Reeves, Julie D.
d5726d5e-a628-4c71-bfdd-bd6887d5fb0e
Duke, Veronique M.
d23d86f3-a0ed-42d9-8953-4bd15a333c41
Kottaridis, Panagiotis D.
b83d9bdd-30b7-42c7-afea-ef0d1947fad2
Cwynarski, Kate
34d6aef4-8106-40ee-9609-b44460ccb971
Vassilev, Lyubomir T.
d09777df-25ab-45c1-a9bb-bcdbd0b262ed
Wickremasinghe, R. Gitendra.
9c9c14d3-3ec8-401a-949b-5222c626b165
Steele, Andrew J., Prentice, Archibald G., Hoffbrand, A. Victor, Yogashangary, Birunthini C., Hart, Stephen M., Nacheva, Elisabeth P., Howard-Reeves, Julie D., Duke, Veronique M., Kottaridis, Panagiotis D., Cwynarski, Kate, Vassilev, Lyubomir T. and Wickremasinghe, R. Gitendra.
(2008)
p53-mediated apoptosis of CLL cells: evidence for a transcription-independent mechanism.
Blood, 112 (9), .
(doi:10.1182/blood-2008-05-156380).
(PMID:18948584)
Abstract
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 alpha, an inhibitor of p53-mediated transcription, blocked the up-regulation of Puma and also of p21(CIP1). Surprisingly, pifithrin alpha 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.
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e-pub ahead of print date: 5 August 2008
Published date: 1 November 2008
Organisations:
Cancer Sciences
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Local EPrints ID: 178123
URI: http://eprints.soton.ac.uk/id/eprint/178123
ISSN: 0006-4971
PURE UUID: 90d1899b-6060-469d-a1a3-09f96a95c5ab
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Date deposited: 23 Mar 2011 09:56
Last modified: 14 Mar 2024 02:57
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Contributors
Author:
Archibald G. Prentice
Author:
A. Victor Hoffbrand
Author:
Birunthini C. Yogashangary
Author:
Stephen M. Hart
Author:
Elisabeth P. Nacheva
Author:
Julie D. Howard-Reeves
Author:
Veronique M. Duke
Author:
Panagiotis D. Kottaridis
Author:
Kate Cwynarski
Author:
Lyubomir T. Vassilev
Author:
R. Gitendra. Wickremasinghe
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