P53 INDUCTION IS ASSOCIATED WITH NEURONAL DAMAGE IN THE CENTRAL-NERVOUS-SYSTEM

The p53 tumor-suppressor gene encodes a growth-regulatory protein that has been implicated in programmed cell death. To investigate the possible role of p53 in neuronal death, we studied p53 expression associated with excitotoxicity in the adult rat brain. Within hours of systemic administration of the glutamate analogue kainic acid, p53 mRNA levels were increased in neurons exhibiting morphological features of damage within kainate-vulnerable brain regions. A similar distribution was found for neurons exhibiting DNA damage as evidenced by in situ end-labeling of fragmented DNA. Pretreatment with the protein synthesis inhibitor cycloheximide prevented both kainate-mediated p53 induction and neuronal damage. The distinctive pattern of excitotoxin-mediated p53 expression suggests that p53 induction is a marker of irreversible injury in postmitotic cells of the central nervous system and could have functional significance in determining selective neuronal vulnerability.