P53 is essential for developmental neuron death as regulated by the TrkA and p75 neurotrophin receptors

Naturally occurring sympathetic neuron death is the result of two apoptotic signaling events: one normally suppressed by NGF/TrkA survival signals, an d a second activated by the p75 neurotrophin receptor. Here we demonstrate that the p53 tumor suppressor protein, likely as induced by the MEKK-JNK pa thway, is an essential component of both of these apoptotic signaling casca des. In cultured neonatal sympathetic neurons, p53 protein levels are eleva ted in response to both NGF withdrawal and p75NTR activation. NGF withdrawa l also results in elevation of a known p53 target, the apoptotic protein Ba r. Functional ablation of p53 using the adenovirus E1B55K protein inhibits neuronal apoptosis as induced by either NGF withdrawal or p75 activation. D irect stimulation of the MEKK-JNK pathway using activated MEKK1 has similar effects; p53 and Bar are increased and the subsequent neuronal apoptosis c an be rescued by E1B55K. Expression of p53 in sympathetic neurons indicates that p53 functions downstream of JNK and upstream of Bar. Finally, when p5 3 levels are reduced or absent in p53+/- or p53-/- mice, naturally occurrin g sympathetic neuron death is inhibited. Thus, p53 is an essential common c omponent of two receptor-mediated signal transduction cascades that converg e on the MEKK-JNK pathway to regulate the developmental death of sympatheti c neurons.