Neuronal life and death: an essential role for the p53 family

Recent evidence indicates that the p53 tumor suppressor protein, and its re lated family member, p73, play an essential role in regulating neuronal apo ptosis in both the developing and injured, mature nervous system. In the de veloping nervous system, they do so by regulating naturally-occurring cell death in neural progenitor cells and in postmitotic neurons, acting to ensu re the apoptosis of cells that either do not appropriately undergo the prog enitor to postmitotic neuron transition, or that fail to compete for suffic ient quantities of trophic support. Somewhat surprisingly, in developing po stmitotic neurons, p53 plays a proapoptotic role, while a naturally-occurri ng, truncated form of p73, Delta Np73, antagonizes p53 and plays an anti-ap optotic role. In the mature nervous system, numerous studies indicate that p53 is essential for the neuronal death in response to a variety of insults , including DNA damage, ischemia and excitotoxicity. It is likely that all of these insults culminate in DNA damage, which may well be a common trigge r for neuronal apoptosis, In this regard, the signaling pathways that are r esponsible for triggering p53 dependent neuronal apoptosis are starting to be elucidated, and involve cell cycle deregulation and activation of the JN K pathway, Finally, accumulating evidence indicates that p53 is perturbed i n the CNS in a number of neurodegenerative disorders, leading to the hypoth esis that longterm oxidative damage and/or excitotoxicity ultimately trigge r p53 dependent apoptosis in the chronically degenerating nervous system.