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DAPK1-p53 interaction converges necrotic and apoptotic pathways of ischemic neuronal death.
- Source :
-
The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2014 May 07; Vol. 34 (19), pp. 6546-56. - Publication Year :
- 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 (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(DDΔ)) 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.
- Subjects :
- Animals
Cell Hypoxia physiology
Cells, Cultured
Cloning, Molecular
Peptidyl-Prolyl Isomerase F
Cyclophilins metabolism
Death-Associated Protein Kinases genetics
Death-Associated Protein Kinases metabolism
Dependovirus genetics
Gene Deletion
Glucose genetics
Glutathione Transferase metabolism
Immunoprecipitation
Luciferases genetics
Male
Mice
Mice, Inbred C57BL
Protein Binding
Real-Time Polymerase Chain Reaction
Tumor Suppressor Protein p53 genetics
bcl-2-Associated X Protein biosynthesis
bcl-2-Associated X Protein genetics
Apoptosis genetics
Brain Ischemia genetics
Brain Ischemia pathology
Death-Associated Protein Kinases physiology
Necrosis genetics
Neurons pathology
Signal Transduction genetics
Tumor Suppressor Protein p53 physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1529-2401
- Volume :
- 34
- Issue :
- 19
- Database :
- MEDLINE
- Journal :
- The Journal of neuroscience : the official journal of the Society for Neuroscience
- Publication Type :
- Academic Journal
- Accession number :
- 24806680
- Full Text :
- https://doi.org/10.1523/JNEUROSCI.5119-13.2014