A role for the tumour suppressor gene p53 in regulating neuronal apoptosis

The tumour suppressor gene p53 is a nuclear phosphoprotein whose correct functioning is crucial for an appropriate cellular response to DNA damage. It has been suggested that p53 may act as a 'guardian of the genome' since when DNA damage is mild, p53 functions to halt cell cycle progression allowing DNA repair to occur before progression through the cell cycle. This prevents 'fixing' of lesions into the genome during replication. However when DNA damage is severe and irreversible, p53 induces the cell to undergo apoptosis. Recent studies have demonstrated DNA fragmentation and increased expression of p53 within neurons after injury. It appears that p53 expression may precede DNA fragmentation suggesting that rather than being induced in neurons in response to DNA damage, p53 expression may actually initiate neuronal apoptosis leading to DNA fragmentation. Recent reports documenting the resistance of neurons derived from p53-null mice (p53-/-) to excitotoxicity and DNA damaging agents both in vitro and in vivo and showing that p53 overexpression induces neuronal apoptosis in vitro support a role for the tumour suppressor gene p53 in regulating neuronal apoptosis. Here we review the recent evidence and discuss likely mechanisms involved in p53-mediated neuronal apoptosis.