Bax-Dependent Caspase-3 Activation Is a Key Determinant in p53-Induced Apoptosis in Neurons

p53 is a pivotal molecule regulating the death of neurons both after acute injury and during development. The molecular mechanisms by which p53 induces apoptosis in neuronal cells, however, are not well understood. We have shown previously that adenovirus-mediated p53 gene delivery to neurons was su...

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Bibliographic Details
Published in:The Journal of neuroscience 1999-09, Vol.19 (18), p.7860-7869
Main Authors: Cregan, Sean P, MacLaurin, Jason G, Craig, Constance G, Robertson, George S, Nicholson, Donald W, Park, David S, Slack, Ruth S
Format: Article
Language:English
Subjects:
Adenoviridae
Animals
Animals, Newborn
Apoptosis
bcl-2-Associated X Protein
Brain - cytology
Brain - physiology
Caspase 3
Caspases - genetics
Caspases - metabolism
Cells, Cultured
Cerebellum - cytology
Cerebellum - physiology
Genes, p53
Kinetics
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Neurons - cytology
Neurons - physiology
Proto-Oncogene Proteins - genetics
Proto-Oncogene Proteins - physiology
Proto-Oncogene Proteins c-bcl-2
Tumor Suppressor Protein p53 - genetics
Tumor Suppressor Protein p53 - metabolism
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Summary:p53 is a pivotal molecule regulating the death of neurons both after acute injury and during development. The molecular mechanisms by which p53 induces apoptosis in neuronal cells, however, are not well understood. We have shown previously that adenovirus-mediated p53 gene delivery to neurons was sufficient to induce apoptosis. In the present study we have examined the molecular mechanism by which p53 evokes neuronal cell death. Adenovirus-mediated delivery of p53 to cerebellar granule neurons resulted in caspase-3 (CPP32) activation followed by terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL) staining and loss of viability as determined by an MTT survival assay. To determine whether Bax is essential for caspase-3 activation, p53 was expressed in Bax-deficient cells. Bax null neurons did not exhibit caspase-3 activation in response to p53 and were protected from apoptosis. To determine whether Bax-dependent caspase-3 activation was required in p53-mediated neuronal cell death, caspase-3-deficient neurons were examined. Our results indicate that caspase-3-deficient neurons exhibit a remarkable delay in apoptosis and a dramatic decrease in TUNEL-positive cells. These studies demonstrate that p53-induced cell death in postmitotic neurons involves a Bax-dependent caspase-3 activation, suggesting that these molecules are important determinants in neuronal cell death after injury.
ISSN:0270-6474
1529-2401
DOI:10.1523/jneurosci.19-18-07860.1999