DAPK1-p53 Interaction Converges Necrotic and Apoptotic Pathways of Ischemic Neuronal Death
DAPK1-p53 Interaction Converges Necrotic and Apoptotic Pathways of Ischemic Neuronal Death
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DAPK1-p53 相互作用汇聚缺血性神经元死亡的坏死和凋亡途径
DOI：
10.1523/jneurosci.5119-13.2014
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发表时间：
2014-05-07
影响因子：
5.3
通讯作者：
Lu, Youming
中科院分区：
文献类型：
--
作者：
Pei, Lei;Shang, You;Lu, Youming
坏死和凋亡是介导缺血性损伤的两种不同类型的机制。但它们之间的信号点尚未确定。在这里，我们发现活化的死亡相关蛋白激酶1（DAPK 1）通过DAPK 1死亡结构域（DAPK 1DD）与p53的DNA结合基序（p53 DM）的直接结合，磷酸化p53的丝氨酸-23（pS（23））。我们发现，pS（23）作为p53的功能版本，并介导坏死和凋亡神经元死亡;在细胞核中，pS（23）诱导促凋亡基因的表达，如Bax，而在线粒体基质中，pS（23）通过与亲环素D（CypD）在培养的小鼠皮层神经元中的相互作用引发坏死。缺失DAPK 1DD（DAPK 1（DD Delta））或应用Tat-p53 DM中断DAPK 1-p53相互作用阻断小鼠皮层神经元中pS（23）作用的这些双重途径。因此，DAPK 1-p53相互作用是坏死和凋亡途径会聚的信号点，并且是治疗缺血性损伤的理想靶点。
Necrosis and apoptosis are two distinct types of mechanisms that mediate ischemic injury. But a signaling point of convergence between them has yet to be identified. Here, we show that activated death-associated protein kinase 1 (DAPK1), phosphorylates p53 at serine-23 (pS(23)) via a direct binding of DAPK1 death domain (DAPK1DD) to the DNA binding motif of p53 (p53DM). We uncover that the pS(23) acts as a functional version of p53 and mediates necrotic and apoptotic neuronal death; in the nucleus, pS(23) induces the expression of proapoptotic genes, such as Bax, whereas in the mitochondrial matrix, pS(23) triggers necrosis via interaction with cyclophilin D (CypD) in cultured cortical neurons from mice. Deletion of DAPK1DD (DAPK1(DD Delta)) or application of Tat-p53DM that interrupts DAPK1-p53 interaction blocks these dual pathways of pS(23) actions in mouse cortical neurons. Thus, the DAPK1-p53 interaction is a signaling point of convergence of necrotic and apoptotic pathways and is a desirable target for the treatment of ischemic insults.