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Science 289 (5477): 304-306

Copyright © 2000 by the American Association for the Advancement of Science

An Anti-Apoptotic Role for the p53 Family Member, p73, During Developmental Neuron Death

Christine D. Pozniak, 1 Stevo Radinovic, 2 Annie Yang, 3 Frank McKeon, 3 David R. Kaplan, 12 Freda D. Miller 1*

p53 plays an essential pro-apoptotic role, a function thought to be shared with its family members p73 and p63. Here, we show that p73 is primarily present in developing neurons as a truncated isoform whose levels are dramatically decreased when sympathetic neurons apoptose after nerve growth factor (NGF) withdrawal. Increased expression of truncated p73 rescues these neurons from apoptosis induced by NGF withdrawal or p53 overexpression. In p73-/- mice, all isoforms of p73 are deleted and the apoptosis of developing sympathetic neurons is greatly enhanced. Thus, truncated p73 is an essential anti-apoptotic protein in neurons, serving to counteract the pro-apoptotic function of p53.

1 Center for Neuronal Survival,
2 Brain Tumor Research Center, Montreal Neurological Institute, McGill University, Montreal, Canada H3A 2B4.
3 Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
*   To whom correspondence should be addressed. E-mail: mdfm{at}musica.mcgill.ca

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K.-i. Watanabe, T. Ozaki, T. Nakagawa, K. Miyazaki, M. Takahashi, M. Hosoda, S. Hayashi, S. Todo, and A. Nakagawara (2002)
J. Biol. Chem. 277, 15113-15123
   Abstract »    Full Text »    PDF »
Autoinhibitory Regulation of p73 by {Delta}Np73 To Modulate Cell Survival and Death through a p73-Specific Target Element within the {Delta}Np73 Promoter.
T. Nakagawa, M. Takahashi, T. Ozaki, K.-i. Watanabe, S. Todo, H. Mizuguchi, T. Hayakawa, and A. Nakagawara (2002)
Mol. Cell. Biol. 22, 2575-2585
   Abstract »    Full Text »    PDF »
Transactivation-deficient Delta TA-p73 Inhibits p53 by Direct Competition for DNA Binding. IMPLICATIONS FOR TUMORIGENESIS.
T. Stiewe, C. C. Theseling, and B. M. Putzer (2002)
J. Biol. Chem. 277, 14177-14185
   Abstract »    Full Text »    PDF »
Possible Oncogenic Potential of {Delta}Np73: A Newly Identified Isoform of Human p73.
O. Ishimoto, C. Kawahara, K. Enjo, M. Obinata, T. Nukiwa, and S. Ikawa (2002)
Cancer Res. 62, 636-641
   Abstract »    Full Text »    PDF »
N-myc Promotes Survival and Induces S-Phase Entry of Postmitotic Sympathetic Neurons.
K. Wartiovaara, F. Barnabe-Heider, F. D. Miller, and D. R. Kaplan (2002)
J. Neurosci. 22, 815-824
   Abstract »    Full Text »    PDF »
The Transcriptional Repressor ZEB Regulates p73 Expression at the Crossroad between Proliferation and Differentiation.
G. Fontemaggi, A. Gurtner, S. Strano, Y. Higashi, A. Sacchi, G. Piaggio, and G. Blandino (2001)
Mol. Cell. Biol. 21, 8461-8470
   Abstract »    Full Text »    PDF »
Cyclin-Dependent Kinases and P53 Pathways Are Activated Independently and Mediate Bax Activation in Neurons after DNA Damage.
E. J. Morris, E. Keramaris, H. J. Rideout, R. S. Slack, N. J. Dyson, L. Stefanis, and D. S. Park (2001)
J. Neurosci. 21, 5017-5026
   Abstract »    Full Text »    PDF »
p53 Family Update: p73 and p63 Develop Their Own Identities.
M. S. Irwin and W. G. Kaelin (2001)
Cell Growth Differ. 12, 337-349
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p53 associates with and targets {Delta}Np63 into a protein degradation pathway.
E. A. Ratovitski, M. Patturajan, K. Hibi, B. Trink, K. Yamaguchi, and D. Sidransky (2001)
PNAS 98, 1817-1822
   Abstract »    Full Text »    PDF »
p300 Does Not Require Its Acetylase Activity to Stimulate p73 Function.
X. Zeng, H. Lee, Q. Zhang, and H. Lu (2001)
J. Biol. Chem. 276, 48-52
   Abstract »    Full Text »    PDF »

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