1. DAPK1–p53 Interaction Converges Necrotic and Apoptotic Pathways of Ischemic Neuronal Death
- Author
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You Shang, Huijuan Jin, Na Wei, Youming Lu, Lei Pei, Ling-Qiang Zhu, Xiaoxi Wang, Shan Wang, Yan Wu, Honglin Yan, and Chengye Yao
- Subjects
Male ,Necrosis ,Apoptosis ,Biology ,Real-Time Polymerase Chain Reaction ,Brain Ischemia ,Cyclophilins ,Mice ,medicine ,Animals ,Immunoprecipitation ,Cloning, Molecular ,Luciferases ,Protein kinase A ,Gene ,Cells, Cultured ,Glutathione Transferase ,bcl-2-Associated X Protein ,Death domain ,Neurons ,General Neuroscience ,Articles ,Dependovirus ,Cell Hypoxia ,Cell biology ,Mice, Inbred C57BL ,Death-Associated Protein Kinases ,Glucose ,medicine.anatomical_structure ,Mitochondrial matrix ,Phosphorylation ,Tumor Suppressor Protein p53 ,medicine.symptom ,Nucleus ,Cyclophilin D ,Gene Deletion ,Protein Binding ,Signal Transduction - Abstract
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 (pS23) via a direct binding of DAPK1 death domain (DAPK1DD) to the DNA binding motif of p53 (p53DM). We uncover that thepS23acts as a functional version of p53 and mediates necrotic and apoptotic neuronal death; in the nucleus,pS23induces the expression of proapoptotic genes, such asBax, whereas in the mitochondrial matrix,pS23triggers necrosis via interaction with cyclophilin D (CypD) in cultured cortical neurons from mice. Deletion of DAPK1DD (DAPK1DDΔ) or application of Tat-p53DM that interrupts DAPK1–p53 interaction blocks these dual pathways ofpS23actions 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.
- Published
- 2014