The p53 tumor suppressor gene is a sequence-specific transcription factor that activates the expression of genes engaged in promoting growth arrest or cell death in response to genotoxic stress. A role for p53-related modulation of neuronal viability has been suggested by the finding that p53 expression is elevated in damaged neurons in acute models of injury such as ischemia and epilepsy and in brain tissue samples derived from patients with chronic neurodegenerative diseases. Moreover, the absence of p53 has now been shown to protect neurons from a wide variety of acute toxic insults consistent with the hypothesis from our previous application that p53 expression regulates neuronal viability after injury. Our long-range objective is to assess the consequences of p53 gene expression in the CNS. In the present application, we propose to test the hypothesis that p53-mediated cell death is regulated by defined changes in gene expression as well as the activation of discrete signaling pathways involving the pro-apoptotic protein Bax with subsequent alterations in mitochondrial integrity. We will specifically: 1) Determine if the p53 protein induces Bax translocation and a loss of mitochondrial integrity; 2) Determine if stress-activated kinases are required for p53 induction or p53-mediated cell death; 3) Identify mechanisms by which p53 contributes to caspase activation; and 4) Identify p53-dependent changes in gene expression associated with neuronal cell death. These studies will help elucidate the mechanism by which p53 regulates neuronal survival and activity in response to injury and neurologic disease.
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