DAPK1-p53 interaction converges necrotic and apoptotic pathways of ischemic neuronal death

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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 the pS23 acts as a functional version of p53 and mediates necrotic and apoptotic neuronal death; in the nucleus, pS23 induces the expression of proapoptotic genes, such as Bax, whereas in the mitochondrial matrix, pS23 triggers 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 of pS23 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. © 2014 the authors.

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APA

Pei, L., Shang, Y., Jin, H., Wang, S., Wei, N., Yan, H., … Lu, Y. (2014). DAPK1-p53 interaction converges necrotic and apoptotic pathways of ischemic neuronal death. Journal of Neuroscience, 34(19), 6546–6556. https://doi.org/10.1523/JNEUROSCI.5119-13.2014

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