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

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.