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DAPK1–p53 Interaction Converges Necrotic and Apoptotic Pathways of Ischemic Neuronal Death
- Source :
- The Journal of Neuroscience. 34:6546-6556
- Publication Year :
- 2014
- Publisher :
- Society for Neuroscience, 2014.
-
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.
- 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
Subjects
Details
- ISSN :
- 15292401 and 02706474
- Volume :
- 34
- Database :
- OpenAIRE
- Journal :
- The Journal of Neuroscience
- Accession number :
- edsair.doi.dedup.....877b3eaa650f2815e008c7d80dff7cb6