INVOLVEMENT OF P53 IN DNA STRAND BREAK-INDUCED APOPTOSIS IN POSTMITOTIC CNS NEURONS

The tumour suppressor p53 gene serves as a critical regulator of the c ell cycle and of apoptosis following the exposure of normal cells to D NA damage. To examine the role of p53 in postmitotic CNS neurons, we c ultured cerebellar neurons from normal wild-type mice and mutant p53-n ull mice under various conditions inducing neuronal death. When cerebe llar neurons from 15- to 16-day postnatal wild-type mice were treated with ionizing radiation or DNA-damaging agents, massive neuron death o ccurred after 24-72 h. In contrast, neurons from p53(-/-) mice evident ly resisted gamma-irradiation and some DNA-damaging agents, such as et oposide and bleomycin. On the other hand, low-K+ medium-induced apopto sis of cerebellar neurons was not affected by p53 status. Neither cell cycle progression nor DNA synthesis occurred during cell death induce d by gamma-irradiation and low-K+ medium, as well as in normal culture s of p53(+/+) and p53(-/-) neurons. These results suggest that p53 is required for the apoptotic death of postmitotic cerebellar neurons ind uced by DNA strand breaks.