A ROLE FOR THE TUMOR-SUPPRESSOR GENE P53 IN REGULATING NEURONAL APOPTOSIS

THE tumour suppressor gene p53 is a nuclear phosphoprotein whose corre ct functioning is crucial for an appropriate cellular response to DNA damage. It has been suggested that p53 may act as a 'guardian of the g enome' since when DNA damage is mild, p53 functions to halt cell cycle progression allowing DNA repair to occur before progression through t he cell cycle. This prevents 'fixing' of lesions into the genome durin g replication. However when DNA damage is severe and irreversible, p53 induces the cell to undergo apoptosis. Recent studies have demonstrat ed DNA fragmentation and increased expression of p53 within neurons af ter injury. It appears that p53 expression may precede DNA fragmentati on suggesting that rather than being induced in neurons in response to DNA damage, p53 expression may actually initiate neuronal apoptosis l eading to DNA fragmentation. Recent reports documenting the resistance of neurons derived from p53-null mice (p53(-/-)) to excitotoxicity an d DNA damaging agents both in vitro and in vivo and showing that p53 o verexpression induces neuronal apoptosis in vitro support a role for t he tumour suppressor gene p53 in regulating neuronal apoptosis. Here w e review the recent evidence and discuss likely mechanisms involved in p53-mediated neuronal apoptosis.