 |
 Previous Article | Next Article 
Volume 16, Number 21,
Issue of November 1, 1996
pp. 6753-6765
Copyright ©1996 Society for Neuroscience
Evidence for p53-Mediated Modulation of Neuronal Viability
Received June 24, 1996; revised Aug. 12, 1996; accepted Aug. 20, 1996.
Hong Xiang1,
Daryl W. Hochman1,
Hideyuki Saya2,
Toshiyoshi Fujiwara3,
Philip A. Schwartzkroin1, and
Richard S. Morrison1
1 Department of Neurological Surgery, University of
Washington School of Medicine, Seattle, Washington 98195-6470, 2 Department of Oncology, Kumamoto University School of
Medicine, Kumamoto 860, Japan, and 3 First Department of
Surgery, Okayama University Medical School, 2-5-1 Shikata-cho, Okayama
700, Japan
A role for p53-related modulation of neuronal viability has been
suggested by the finding that p53 expression is increased in damaged
neurons in models of ischemia and epilepsy. These findings were
recently extended with the demonstration that mice deficient in p53
(``knock-out'' mice) exhibit almost complete protection from
seizure-induced brain injury, whereas wild-type mice display
significant neuronal cell loss in the hippocampus and other brain
regions. Because the p53 knock-out mice used in the latter study
expressed a global p53 deficiency in all cell types, it was not
possible to conclude that protection was conferred by the exclusive
absence of p53 in neurons. Therefore, in the present study, we
determined whether p53 expression in isolated neurons is directly
coupled to a loss of viability associated with excitotoxic challenge.
Primary cultures of hippocampal or cortical neurons were derived from
animals containing p53 (+/+, +/ ) or those deficient in p53 (/).
p53-Deficient neurons appeared identical to wild-type neurons with
respect to morphology, neurofilament expression, and resting levels of
intracellular calcium. Neurons containing at least one copy of p53 were
severely damaged by exposure to kainic acid or glutamate. Cell damage
was assessed by direct cell counting and by nuclear morphology after
propidium iodide staining of DNA. In contrast, neurons deficient in p53
(/) exhibited little or no damage in response to excitotoxin
treatment. Despite their divergent outcomes, p53 (+/+) and p53 (/)
neurons demonstrated similar sustained elevations in intracellular
calcium levels triggered by glutamate exposure. Restoring p53
expression to p53-deficient neurons, using adenovirus-mediated
transduction, was sufficient to promote neuronal cell death even in the
absence of excitotoxin. These results demonstrate a direct relationship
between p53 expression and loss of viability in CNS neurons.
Key words:
p53;
neurons;
brain injury;
epilepsy;
apoptosis;
hippocampus;
excitotoxin;
adenovirus;
Ca2+
This article has been cited by other articles:
|
|
|
|
 
L. J. Martin, Z. Liu, J. Pipino, B. Chestnut, and M. A. Landek
Molecular Regulation of DNA Damage-Induced Apoptosis in Neurons of Cerebral Cortex
Cereb Cortex,
September 26, 2008;
(2008)
bhn167v1.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Hasegawa and K. Yoshikawa
Necdin Regulates p53 Acetylation via Sirtuin1 to Modulate DNA Damage Response in Cortical Neurons
J. Neurosci.,
August 27, 2008;
28(35):
8772 - 8784.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. E. Haque, K. J. Thomas, C. D'Souza, S. Callaghan, T. Kitada, R. S. Slack, P. Fraser, M. R. Cookson, A. Tandon, and D. S. Park
Cytoplasmic Pink1 activity protects neurons from dopaminergic neurotoxin MPTP
PNAS,
February 5, 2008;
105(5):
1716 - 1721.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Steckley, M. Karajgikar, L. B. Dale, B. Fuerth, P. Swan, C. Drummond-Main, M. O. Poulter, S. S. G. Ferguson, A. Strasser, and S. P. Cregan
Puma Is a Dominant Regulator of Oxidative Stress Induced Bax Activation and Neuronal Apoptosis
J. Neurosci.,
November 21, 2007;
27(47):
12989 - 12999.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Uo, Y. Kinoshita, and R. S. Morrison
Apoptotic Actions of p53 Require Transcriptional Activation of PUMA and Do Not Involve a Direct Mitochondrial/Cytoplasmic Site of Action in Postnatal Cortical Neurons
J. Neurosci.,
November 7, 2007;
27(45):
12198 - 12210.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Forte, B. G. Gold, G. Marracci, P. Chaudhary, E. Basso, D. Johnsen, X. Yu, J. Fowlkes, M. Rahder, K. Stem, et al.
Cyclophilin D inactivation protects axons in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis
PNAS,
May 1, 2007;
104(18):
7558 - 7563.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Zhang, D. Qu, E. J. Morris, M. J. O'Hare, S. M. Callaghan, R. S. Slack, H. M. Geller, and D. S. Park
The Chk1/Cdc25A Pathway as Activators of the Cell Cycle in Neuronal Death Induced by Camptothecin.
J. Neurosci.,
August 23, 2006;
26(34):
8819 - 8828.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Endo, H. Kamada, C. Nito, T. Nishi, and P. H. Chan
Mitochondrial translocation of p53 mediates release of cytochrome c and hippocampal CA1 neuronal death after transient global cerebral ischemia in rats.
J. Neurosci.,
July 26, 2006;
26(30):
7974 - 7983.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Klochendler-Yeivin, E. Picarsky, and M. Yaniv
Increased DNA Damage Sensitivity and Apoptosis in Cells Lacking the Snf5/Ini1 Subunit of the SWI/SNF Chromatin Remodeling Complex.
Mol. Cell. Biol.,
April 1, 2006;
26(7):
2661 - 2674.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. K. Wong, M. Fricker, A. Wyttenbach, A. Villunger, E. M. Michalak, A. Strasser, and A. M. Tolkovsky
Mutually Exclusive Subsets of BH3-Only Proteins Are Activated by the p53 and c-Jun N-Terminal Kinase/c-Jun Signaling Pathways during Cortical Neuron Apoptosis Induced by Arsenite
Mol. Cell. Biol.,
October 1, 2005;
25(19):
8732 - 8747.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. J. O'Hare, N. Kushwaha, Y. Zhang, H. Aleyasin, S. M. Callaghan, R. S. Slack, P. R. Albert, I. Vincent, and D. S. Park
Differential Roles of Nuclear and Cytoplasmic Cyclin-Dependent Kinase 5 in Apoptotic and Excitotoxic Neuronal Death
J. Neurosci.,
September 28, 2005;
25(39):
8954 - 8966.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Uo, Y. Kinoshita, and R. S. Morrison
Neurons Exclusively Express N-Bak, a BH3 Domain-only Bak Isoform That Promotes Neuronal Apoptosis
J. Biol. Chem.,
March 11, 2005;
280(10):
9065 - 9073.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Stefanis
Caspase-Dependent and -Independent Neuronal Death: Two Distinct Pathways to Neuronal Injury
Neuroscientist,
February 1, 2005;
11(1):
50 - 62.
[Abstract]
[PDF]
|
|
|
|
|
|
|
H. Wang, S.-W. Yu, D. W. Koh, J. Lew, C. Coombs, W. Bowers, H. J. Federoff, G. G. Poirier, T. M. Dawson, and V. L. Dawson
Apoptosis-Inducing Factor Substitutes for Caspase Executioners in NMDA-Triggered Excitotoxic Neuronal Death
J. Neurosci.,
December 1, 2004;
24(48):
10963 - 10973.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Sugo, N. Niimi, Y. Aratani, K. Takiguchi-Hayashi, and H. Koyama
p53 Deficiency Rescues Neuronal Apoptosis but Not Differentiation in DNA Polymerase {beta}-Deficient Mice
Mol. Cell. Biol.,
November 1, 2004;
24(21):
9470 - 9477.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. B. Jacobs, G. S. Walsh, and F. D. Miller
Neuronal Survival and p73/p63/p53: A Family Affair
Neuroscientist,
October 1, 2004;
10(5):
443 - 455.
[Abstract]
[PDF]
|
|
|
|
|
|
|
A. Fortin, J. G. MacLaurin, N. Arbour, S. P. Cregan, N. Kushwaha, S. M. Callaghan, D. S. Park, P. R. Albert, and R. S. Slack
The Proapoptotic Gene SIVA Is a Direct Transcriptional Target for the Tumor Suppressors p53 and E2F1
J. Biol. Chem.,
July 2, 2004;
279(27):
28706 - 28714.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. D. Johnson, L.-R. Yu, T. P. Conrads, Y. Kinoshita, T. Uo, J. D. Matthews, S.-W. Lee, R. D. Smith, T. D. Veenstra, and R. S. Morrison
Proteome Analysis of DNA Damage-induced Neuronal Death Using High Throughput Mass Spectrometry
J. Biol. Chem.,
June 18, 2004;
279(25):
26685 - 26697.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L.-W. Jin, I. Maezawa, I. Vincent, and T. Bird
Intracellular Accumulation of Amyloidogenic Fragments of Amyloid-{beta} Precursor Protein in Neurons with Niemann-Pick Type C Defects Is Associated with Endosomal Abnormalities
Am. J. Pathol.,
March 1, 2004;
164(3):
975 - 985.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Verdaguer, A. Jimenez, A. M. Canudas, E. G. Jorda, F. X. Sureda, M. Pallas, and A. Camins
Inhibition of Cell Cycle Pathway by Flavopiridol Promotes Survival of Cerebellar Granule Cells after an Excitotoxic Treatment
J. Pharmacol. Exp. Ther.,
February 1, 2004;
308(2):
609 - 616.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Keramaris, A. Hirao, R. S. Slack, T. W. Mak, and D. S. Park
Ataxia Telangiectasia-mutated Protein Can Regulate p53 and Neuronal Death Independent of Chk2 in Response to DNA Damage
J. Biol. Chem.,
September 26, 2003;
278(39):
37782 - 37789.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Sedarous, E. Keramaris, M. O'Hare, E. Melloni, R. S. Slack, J. S. Elce, P. A. Greer, and D. S. Park
Calpains Mediate p53 Activation and Neuronal Death Evoked by DNA Damage
J. Biol. Chem.,
July 3, 2003;
278(28):
26031 - 26038.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Vuletic, L.-W. Jin, S. M. Marcovina, E. R. Peskind, T. Moller, and J. J. Albers
Widespread distribution of PLTP in human CNS: evidence for PLTP synthesis by glia and neurons, and increased levels in Alzheimer's disease
J. Lipid Res.,
June 1, 2003;
44(6):
1113 - 1123.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Liu, H. Guo, J. H. Griffin, J. A. Fernandez, and B. V. Zlokovic
Protein S Confers Neuronal Protection During Ischemic/Hypoxic Injury in Mice
Circulation,
April 8, 2003;
107(13):
1791 - 1796.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. ZHU, K. JIN, X. O. MAO, and D. A. GREENBERG
Vascular endothelial growth factor promotes proliferation of cortical neuron precursors by regulating E2F expression
FASEB J,
February 1, 2003;
17(2):
186 - 193.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. D. Pozniak, F. Barnabe-Heider, V. V. Rymar, A. F. Lee, A. F. Sadikot, and F. D. Miller
p73 Is Required for Survival and Maintenance of CNS Neurons
J. Neurosci.,
November 15, 2002;
22(22):
9800 - 9809.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. H. Ghahremani, E. Keramaris, T. Shree, Z. Xia, R. J. Davis, R. Flavell, R. S. Slack, and D. S. Park
Interaction of the c-Jun/JNK Pathway and Cyclin-dependent Kinases in Death of Embryonic Cortical Neurons Evoked by DNA Damage
J. Biol. Chem.,
September 13, 2002;
277(38):
35586 - 35596.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. P. Cregan, A. Fortin, J. G. MacLaurin, S. M. Callaghan, F. Cecconi, S.-W. Yu, T. M. Dawson, V. L. Dawson, D. S. Park, G. Kroemer, et al.
Apoptosis-inducing factor is involved in the regulation of caspase-independent neuronal cell death
J. Cell Biol.,
August 5, 2002;
158(3):
507 - 517.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Zhu, X. O. Mao, Y. Sun, Z. Xia, and D. A. Greenberg
p38 Mitogen-activated Protein Kinase Mediates Hypoxic Regulation of Mdm2 and p53 in Neurons
J. Biol. Chem.,
June 14, 2002;
277(25):
22909 - 22914.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. D. Johnson, X. Wu, N. Aithmitti, and R. S. Morrison
Peg3/Pw1 Is a Mediator between p53 and Bax in DNA Damage-induced Neuronal Death
J. Biol. Chem.,
June 14, 2002;
277(25):
23000 - 23007.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Yamaguchi, M. Taniguchi, O. Hori, S. Ogawa, N. Tojo, N. Matsuoka, S.-i. Miyake, K. Kasai, H. Sugimoto, M. Tamatani, et al.
Peg3/Pw1 Is Involved in p53-mediated Cell Death Pathway in Brain Ischemia/Hypoxia
J. Biol. Chem.,
January 4, 2002;
277(1):
623 - 629.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
E. J. Morris, E. Keramaris, H. J. Rideout, R. S. Slack, N. J. Dyson, L. Stefanis, and D. S. Park
Cyclin-Dependent Kinases and P53 Pathways Are Activated Independently and Mediate Bax Activation in Neurons after DNA Damage
J. Neurosci.,
July 15, 2001;
21(14):
5017 - 5026.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Kataoka, N. Kume, S. Miyamoto, M. Minami, M. Morimoto, K. Hayashida, N. Hashimoto, and T. Kita
Oxidized LDL Modulates Bax/Bcl-2 Through the Lectinlike Ox-LDL Receptor-1 in Vascular Smooth Muscle Cells
Arterioscler. Thromb. Vasc. Biol.,
June 1, 2001;
21(6):
955 - 960.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Ghatan, S. Larner, Y. Kinoshita, M. Hetman, L. Patel, Z. Xia, R. J. Youle, and R. S. Morrison
p38 MAP Kinase Mediates Bax Translocation in Nitric Oxide-induced Apoptosis in Neurons
J. Cell Biol.,
July 24, 2000;
150(2):
335 - 348.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Tanaka, I. Tatsuno, D. Uchida, I. Moroo, H. Morio, S. Nakamura, Y. Noguchi, T. Yasuda, M. Kitagawa, Y. Saito, et al.
Geranylgeranyl-Pyrophosphate, an Isoprenoid of Mevalonate Cascade, Is a Critical Compound for Rat Primary Cultured Cortical Neurons to Protect the Cell Death Induced by 3-Hydroxy-3-Methylglutaryl-CoA Reductase Inhibition
J. Neurosci.,
April 15, 2000;
20(8):
2852 - 2859.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Giovanni, E. Keramaris, E. J. Morris, S. T. Hou, M. O'Hare, N. Dyson, G. S. Robertson, R. S. Slack, and D. S. Park
E2F1 Mediates Death of B-amyloid-treated Cortical Neurons in a Manner Independent of p53 and Dependent on Bax and Caspase 3
J. Biol. Chem.,
April 14, 2000;
275(16):
11553 - 11560.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. E. Mazzoni, F. A. Said, R. Aloyz, F. D. Miller, and D. Kaplan
Ras Regulates Sympathetic Neuron Survival by Suppressing the p53-Mediated Cell Death Pathway
J. Neurosci.,
November 15, 1999;
19(22):
9716 - 9727.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R.-W. Chen, P. A. Saunders, H. Wei, Z. Li, P. Seth, and D.-M. Chuang
Involvement of Glyceraldehyde-3-Phosphate Dehydrogenase (GAPDH) and p53 in Neuronal Apoptosis: Evidence That GAPDH Is Upregulated by p53
J. Neurosci.,
November 1, 1999;
19(21):
9654 - 9662.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. P. Cregan, J. G. MacLaurin, C. G. Craig, G. S. Robertson, D. W. Nicholson, D. S. Park, and R. S. Slack
Bax-Dependent Caspase-3 Activation Is a Key Determinant in p53-Induced Apoptosis in Neurons
J. Neurosci.,
September 15, 1999;
19(18):
7860 - 7869.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. I. Savitz and D. M. Rosenbaum
Review : Gene Expression after Cerebral Ischemia
Neuroscientist,
July 1, 1999;
5(4):
238 - 253.
[Abstract]
[PDF]
|
|
|
|
|
|
|
X. Xu, D. Yang, T. Wyss-Coray, J. Yan, L. Gan, Y. Sun, and L. Mucke
Wild-type but not Alzheimer-mutant amyloid precursor protein confers resistance against p53-mediated apoptosis
PNAS,
June 22, 1999;
96(13):
7547 - 7552.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Taniura, K. Matsumoto, and K. Yoshikawa
Physical and Functional Interactions of Neuronal Growth Suppressor Necdin with p53
J. Biol. Chem.,
June 4, 1999;
274(23):
16242 - 16248.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Z.-H. Qin, R.-W. Chen, Y. Wang, M. Nakai, D.-M. Chuang, and T. N. Chase
Nuclear Factor kappa B Nuclear Translocation Upregulates c-Myc and p53 Expression during NMDA Receptor-Mediated Apoptosis in Rat Striatum
J. Neurosci.,
May 15, 1999;
19(10):
4023 - 4033.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. D. Johnson, Y. Kinoshita, H. Xiang, S. Ghatan, and R. S. Morrison
Contribution of p53-Dependent Caspase Activation to Neuronal Cell Death Declines with Neuronal Maturation
J. Neurosci.,
April 15, 1999;
19(8):
2996 - 3006.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Stempien-Otero, A. Karsan, C. J. Cornejo, H. Xiang, T. Eunson, R. S. Morrison, M. Kay, R. Winn, and J. Harlan
Mechanisms of Hypoxia-induced Endothelial Cell Death. ROLE OF p53 IN APOPTOSIS
J. Biol. Chem.,
March 19, 1999;
274(12):
8039 - 8045.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Berger, F. H. Gage, and S. Vijayaraghavan
Nicotinic Receptor-Induced Apoptotic Cell Death of Hippocampal Progenitor Cells
J. Neurosci.,
September 1, 1998;
18(17):
6871 - 6881.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. C.-K. Chan, T. R. Hinds, S. Impey, and D. R. Storm
Hippocampal Neurotoxicity of Delta 9-Tetrahydrocannabinol
J. Neurosci.,
July 15, 1998;
18(14):
5322 - 5332.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Xiang, Y. Kinoshita, C. M. Knudson, S. J. Korsmeyer, P. A. Schwartzkroin, and R. S. Morrison
Bax Involvement in p53-Mediated Neuronal Cell Death
J. Neurosci.,
February 15, 1998;
18(4):
1363 - 1373.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Lakkaraju, J. M. Dubinsky, W. C. Low, and Y.-E. Rahman
Neurons Are Protected from Excitotoxic Death by p53 Antisense Oligonucleotides Delivered in Anionic Liposomes
J. Biol. Chem.,
August 17, 2001;
276(34):
32000 - 32007.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Fortin, S. P. Cregan, J. G. MacLaurin, N. Kushwaha, E. S. Hickman, C. S. Thompson, A. Hakim, P. R. Albert, F. Cecconi, K. Helin, et al.
APAF1 is a key transcriptional target for p53 in the regulation of neuronal cell death
J. Cell Biol.,
October 15, 2001;
155(2):
207 - 216.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
