p53 is essential for developmental neuron death as regulated by the TrkA and p75 neurotrophin receptors.
p53 is essential for developmental neuron death as regulated by the TrkA and p75 neurotrophin receptors.
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p53对于受TRKA和p75神经营养蛋白受体调节的发育神经元死亡至关重要。
DOI：
10.1083/jcb.143.6.1691
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发表时间：
1998-12-14
影响因子：
7.8
通讯作者：
Miller, F D
中科院分区：
文献类型：
--
作者：
Aloyz, R S;Bamji, S X;Pozniak, C D;Toma, J G;Atwal, J;Kaplan, D R;Miller, F D
自然发生的交感神经元死亡是两个凋亡信号事件的结果：一个通常被NGF/TrkA存活信号抑制，第二个被p75神经营养因子受体激活。在这里，我们证明了p53肿瘤抑制蛋白，可能是由MEKK-JNK途径诱导的，是这两个凋亡信号级联的重要组成部分。在培养的新生交感神经元中，p53蛋白水平响应于NGF撤除和p75 NTR激活而升高。神经生长因子撤退也导致升高的一个已知的p53的目标，凋亡蛋白Bax。使用腺病毒E1 B55 K蛋白的p53功能性消融抑制由NGF撤除或p75激活诱导的神经元凋亡。使用活化的MEKK 1直接刺激MEKK-JNK通路具有类似的效果; p53和Bax增加，并且随后的神经元凋亡可以被E1 B55 K拯救。p53在交感神经元中的表达表明p53在JNK下游和Bax上游起作用。最后，当p53+/-或p53-/-小鼠中p53水平降低或缺失时，自然发生的交感神经元死亡被抑制。因此，p53是两个受体介导的信号转导级联的重要共同组分，其汇聚在MEKK-JNK通路上以调节交感神经元的发育性死亡。
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.