title: p53 is essential for developmental neuron death as regulated by the TrkA and p75 neurotrophin receptors.
abstract: Naturally occurring sympathetic neuron death is the result of two apoptotic signaling events: one normally suppressed by NGF/TrkA survival signals, and a second activated by the p75 neurotrophin receptor. Here we demonstrate that the p53 tumor suppressor protein, likely as induced by the MEKK-JNK pathway, is an essential component of both of these apoptotic signaling cascades. In cultured neonatal sympathetic neurons, p53 protein levels are elevated in response to both NGF withdrawal and p75NTR activation. NGF withdrawal also results in elevation of a known p53 target, the apoptotic protein Bax. Functional ablation of p53 using the adenovirus E1B55K protein inhibits neuronal apoptosis as induced by either NGF withdrawal or p75 activation. Direct stimulation of the MEKK-JNK pathway using activated MEKK1 has similar effects; p53 and Bax are increased and the subsequent neuronal apoptosis can be rescued by E1B55K. Expression of p53 in sympathetic neurons indicates that p53 functions downstream of JNK and upstream of Bax. Finally, when p53 levels are reduced or absent in p53+/- or p53-/- mice, naturally occurring sympathetic neuron death is inhibited. Thus, p53 is an essential common component of two receptor-mediated signal transduction cascades that converge on the MEKK-JNK pathway to regulate the developmental death of sympathetic neurons.
authors.affiliation: Center for Neuronal Survival, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada H3A 2B4.
authors.forename: R S
authors.initials: RS
authors.lastname: Aloyz
authors.forename: S X
authors.initials: SX
authors.lastname: Bamji
authors.forename: C D
authors.initials: CD
authors.lastname: Pozniak
authors.forename: J G
authors.initials: JG
authors.lastname: Toma
authors.forename: J
authors.initials: J
authors.lastname: Atwal
authors.forename: D R
authors.initials: DR
authors.lastname: Kaplan
authors.forename: F D
authors.initials: FD
authors.lastname: Miller
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D016923:Cell Death; D002478:Cells, Cultured; D048031:JNK Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases; D008959:Models, Neurological; D009414:Nerve Growth Factors / Q000494:pharmacology / Q000502:physiology; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology*; D020800:Receptor, Nerve Growth Factor; D020917:Receptor, trkA; D017475:Receptors, Nerve Growth Factor / Q000502:physiology*; D015398:Signal Transduction; D017783:Superior Cervical Ganglion / Q000166:cytology* / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051028:bcl-2-Associated X Protein
chemical_list: C494827:Bax protein, mouse; C494828:Bax protein, rat; D009414:Nerve Growth Factors; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; C482578:Map3k1 protein, mouse