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.

Receptors that mediate cellular dependence

“…[72][73][74][75] TrkA was initially shown to be capable of mediating the described responses to NGF, such as neurite outgrowth and neuronal survival, 73 leaving the role of p75 NTR unexplained. Subsequent studies demonstrated that p75 NTR and TrkA collaborate to produce high-affinity sites for NGF binding, and that p75 NTR expression enhances the selectivity of neurotrophin binding for specific Trks (TrkA, B, and C; 76 ).…”

“…90,91 Following the descriptions of apoptosis induction by p75 NTR in the absence of NGF, studies appeared showing that p75 NTR may also induce apoptosis following NGF binding, that is, p75 NTR may also function as a death receptor. 75,78,79 However, despite this apparent functional similarity to Fas and TNFR I, and the similarities in structure of these three proteins, Fas-p75NTR chimeras consisting of the extracellular domain of Fas and the intracellular domain of p75NTR failed to induce apoptosis. 92 Thus, apoptosis induction following NGF binding to p75 NTR is somehow different from following the binding of death factors to Fas and TNFR I.…”

Diverse functions of JNK signaling and c-Jun in stress response and apoptosis

“…A candidate e ector is Fas ligand, which is induced in response to NGF withdrawal and JNK activation in PC12 cells (Le-Niculescu et al, 1999). Other mediators of JNK signaling during apoptosis could be p53 and the apoptotic protein Bax (Aloyz et al, 1998).…”

Mitogen-activated protein kinases as glucose transducers for diabetic complications

“…Where these receptors act in concert, the signalling pathway described above through ERK predominates and the NGF-supported phenotype is maintained, for example in non-myelinated nociceptors [127±129]. A different picture emerges when the p75 neurotrophin receptor is present without trkA, because under these conditions NGF activates JNK and cell death can be a consequence [130,131]. Introduction of trkA removes the link to cell death [132].…”