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Science 302 (5647): 1036-1038

Copyright © 2003 by the American Association for the Advancement of Science

p53- and Drug-Induced Apoptotic Responses Mediated by BH3-Only Proteins Puma and Noxa

Andreas Villunger,1,2* Ewa M. Michalak,1 Leigh Coultas,1 Franziska Müllauer,2 Günther Böck,2 Michael J. Ausserlechner,2 Jerry M. Adams,1 Andreas Strasser1*

Abstract: Apoptosis provoked by DNA damage requires the p53 tumor suppressor, but which of the many p53-regulated genes are required has remained unknown. Two genes induced by this transcription factor, noxa and puma (bbc3), stand out, because they encode BH3-only proteins, proapoptotic members of the Bcl-2 family required to initiate apoptosis. In mice with either noxa or puma disrupted, we observed decreased DNA damage–induced apoptosis in fibroblasts, although only loss of Puma protected lymphocytes from cell death. Puma deficiency also protected cells against diverse p53-independent cytotoxic insults, including cytokine deprivation and exposure to glucocorticoids, the kinase inhibitor staurosporine, or phorbol ester. Hence, Puma and Noxa are critical mediators of the apoptotic responses induced by p53 and other agents.

1 The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
2 Institute for Pathophysiology, University of Innsbruck, Austria.

* To whom correspondence should be addressed. E-mail: strasser{at} (A.S.) and andreas.villunger{at} (A.V.)

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Reduced hippocampal damage and epileptic seizures after status epilepticus in mice lacking proapoptotic Puma.
T. Engel, B. M. Murphy, S. Hatazaki, E. M. Jimenez-Mateos, C. G. Concannon, I. Woods, J. H. M. Prehn, and D. C. Henshall (2010)
FASEB J 24, 853-861
   Abstract »    Full Text »    PDF »
The Bcl-2 Homology Domain 3 Mimetic ABT-737 Targets the Apoptotic Machinery in Acute Lymphoblastic Leukemia Resulting in Synergistic in Vitro and in Vivo Interactions with Established Drugs.
L. M. High, B. Szymanska, U. Wilczynska-Kalak, N. Barber, R. O'Brien, S. L. Khaw, I. B. Vikstrom, A. W. Roberts, and R. B. Lock (2010)
Mol. Pharmacol. 77, 483-494
   Abstract »    Full Text »    PDF »
Glucose Induces Pancreatic Islet Cell Apoptosis That Requires the BH3-Only Proteins Bim and Puma and Multi-BH Domain Protein Bax.
M. D. McKenzie, E. Jamieson, E. S. Jansen, C. L. Scott, D. C.S. Huang, P. Bouillet, J. Allison, T. W.H. Kay, A. Strasser, and H. E. Thomas (2010)
Diabetes 59, 644-652
   Abstract »    Full Text »    PDF »
Suppression of the Intrinsic Apoptosis Pathway by Synaptic Activity.
F. Leveille, S. Papadia, M. Fricker, K. F. S. Bell, F. X. Soriano, M.-A. Martel, C. Puddifoot, M. Habel, D. J. Wyllie, C. Ikonomidou, et al. (2010)
J. Neurosci. 30, 2623-2635
   Abstract »    Full Text »    PDF »
BclxL Changes Conformation upon Binding to Wild-type but Not Mutant p53 DNA Binding Domain.
F. Hagn, C. Klein, O. Demmer, N. Marchenko, A. Vaseva, U. M. Moll, and H. Kessler (2010)
J. Biol. Chem. 285, 3439-3450
   Abstract »    Full Text »    PDF »
p53 Controls Radiation-Induced Gastrointestinal Syndrome in Mice Independent of Apoptosis.
D. G. Kirsch, P. M. Santiago, E. di Tomaso, J. M. Sullivan, W.-S. Hou, T. Dayton, L. B. Jeffords, P. Sodha, K. L. Mercer, R. Cohen, et al. (2010)
Science 327, 593-596
   Abstract »    Full Text »    PDF »
Myeloid progenitor cells lacking p53 exhibit delayed up-regulation of Puma and prolonged survival after cytokine deprivation.
A. M. Jabbour, C. P. Daunt, B. D. Green, S. Vogel, L. Gordon, R. S. Lee, N. Silke, R. B. Pearson, C. J. Vandenberg, P. N. Kelly, et al. (2010)
Blood 115, 344-352
   Abstract »    Full Text »    PDF »
Role of the translocation partner in protection against AID-dependent chromosomal translocations.
M. Jankovic, D. F. Robbiani, Y. Dorsett, T. Eisenreich, Y. Xu, A. Tarakhovsky, A. Nussenzweig, and M. C. Nussenzweig (2010)
PNAS 107, 187-192
   Abstract »    Full Text »    PDF »
Bim Upregulation by Histone Deacetylase Inhibitors Mediates Interactions with the Bcl-2 Antagonist ABT-737: Evidence for Distinct Roles for Bcl-2, Bcl-xL, and Mcl-1.
S. Chen, Y. Dai, X.-Y. Pei, and S. Grant (2009)
Mol. Cell. Biol. 29, 6149-6169
   Abstract »    Full Text »    PDF »
p16INK4A Sensitizes Human Leukemia Cells to FAS- and Glucocorticoid-induced Apoptosis via Induction of BBC3/Puma and Repression of MCL1 and BCL2.
P. Obexer, J. Hagenbuchner, M. Rupp, C. Salvador, M. Holzner, M. Deutsch, V. Porto, R. Kofler, T. Unterkircher, and M. J. Ausserlechner (2009)
J. Biol. Chem. 284, 30933-30940
   Abstract »    Full Text »    PDF »
Role for Kruppel-Like Factor 4 in Determining the Outcome of p53 Response to DNA Damage.
Q. Zhou, Y. Hong, Q. Zhan, Y. Shen, and Z. Liu (2009)
Cancer Res. 69, 8284-8292
   Abstract »    Full Text »    PDF »
Activation of Tumor Suppressor Protein p53 Is Required for Theiler's Murine Encephalomyelitis Virus-Induced Apoptosis in M1-D Macrophages.
K.-N. Son, S. Pugazhenthi, and H. L. Lipton (2009)
J. Virol. 83, 10770-10777
   Abstract »    Full Text »    PDF »
HDAC2 mediates therapeutic resistance of pancreatic cancer cells via the BH3-only protein NOXA.
P Fritsche, B Seidler, S Schuler, A Schnieke, M Gottlicher, R M Schmid, D Saur, and G Schneider (2009)
Gut 58, 1399-1409
   Abstract »    Full Text »    PDF »
JNK1-dependent PUMA Expression Contributes to Hepatocyte Lipoapoptosis.
S. C. Cazanave, J. L. Mott, N. A. Elmi, S. F. Bronk, N. W. Werneburg, Y. Akazawa, A. Kahraman, S. P. Garrison, G. P. Zambetti, M. R. Charlton, et al. (2009)
J. Biol. Chem. 284, 26591-26602
   Abstract »    Full Text »    PDF »

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