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The Journal of Neuroscience, February 15, 1998, 18(4):1363-1373

Bax Involvement in p53-Mediated Neuronal Cell Death

Hong Xiang¹, Yoshito Kinoshita¹, C. Michael Knudson², Stanley J. Korsmeyer², Philip A. Schwartzkroin¹ and Richard S. Morrison¹

¹ Department of Neurological Surgery, University of Washington School of Medicine, Seattle, Washington 98195-6470, and ² Howard Hughes Medical Institute, Department of Medicine and Pathology, Washington University School of Medicine, St. Louis, Missouri 63110

The tumor suppressor gene p53 has been implicated in the loss of neuronal viability, but the signaling events associated with p53-mediated cell death in cortical and hippocampal neurons are not understood. Previous work has shown that adenovirus-mediated delivery of the p53 gene causes cortical and hippocampal neuronal cell death with some features typical of apoptosis. In the present study we determined whether p53-initiated changes in neuronal viability were dependent on members of the Bcl-2 family of cell death regulators. Primary cultures of cortical neurons were derived from animals containing Bax (+/+ and +/) or those deficient in Bax (/). Cell damage was assessed by direct cell counting and by measurements of MTT activity. Neurons containing at least one copy of the Bax gene were damaged severely by exposure to excitotoxins or by the induction of DNA damage. In contrast, Bax-deficient neurons (/) exhibited significant protection from both types of injury. Bax protein expression was elevated significantly by glutamate exposure, but not by camptothecin-induced DNA damage in wild-type neurons. The glutamate-induced increase in Bax protein was dependent on the presence of the p53 gene. However, increased p53 expression, using adenovirus-mediated transduction, was not sufficient by itself to elevate Bax protein levels. These results demonstrate that Bax is required for neuronal cell death in response to some forms of cytotoxic injury and further support the key role for p53 activation in response to excitotoxic and genotoxic injury.

Key words: Bax; p53; cortical neurons; apoptosis; glutamate; kainate; camptothecin; neuronal cell death

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Copyright © 1998 Society for Neuroscience  0270-6474/98/1841363-11$05.00/0

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