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  • br Funding This work was supported by a research grant

    2019-09-20


    Funding This work was supported by a research grant of the Deutsche Forschungsgemeinschaft (SCHN477-9-2 to R.S.S), the Manfred-Stolte-Stiftung (to R.S.S.) and by a research grant from the German Cancer Aid (Deutsche Krebshilfe, No. 106696/TP 5 to T.F.).
    Introduction Death-associated protein kinase (DAPK), is a serine (Ser)/threonine (Thr) kinase. DAPK has a complex, multi-domain structure that includes a calcium/calmodulin-regulated kinase-domain, a series of ankyrin repeats and carboxyl-terminal death domain. Unlike many other kinases, DAPK is inactivated when it is phosphorylated at Ser308 since the phosphorylation blocks its calmodulin binding site (de Diego et al., 2010). DAPK has been shown to be involved in neuronal death. In PC12 cells, DAPK activity is highly increased upon exposing to apoptotic induction, and inhibition of DAPK activity rescues the cells (Yamamoto et al., 2002). In cultured hippocampal neurons, DAPK level is increased during apoptotic induction (Pelled et al., 2002). DAPK has also been found to be involved in neuronal death in animal ischemia studies. For example, DAPK mRNA expression is up-regulated in rat LX7101 HCL following global ischemia (Shamloo et al., 2005), and DAPK activity is found significantly increased in ischemic-injured rat brain neurons (Schumacher et al., 2002). DAPK knockout mice show dramatic reduction in infarct volume and improved neurological function following cerebral ischemia (Tu et al., 2010). Endoplasmic reticulum (ER) serves important functions in the cell. ER is responsible for post-translational modification of proteins, as well as sorting and exporting these proteins to appropriate destinations. ER is highly sensitive to stresses which result in unfolded protein accumulation in the ER. Upon the accumulation of unfolded proteins, a set of molecular signals for coping with ER stress, collectively termed unfolded protein response (UPR), is activated. The UPR is carried out by three trans-membrane initiator proteins: protein kinase RNA (PKR)-like ER kinase (PERK), inositol-requiring protein-1 (IRE1) and activating transcription factor-6 (ATF6). All these three effector proteins bind to the ER chaperone, Bip (GRP78), on their ER luminal domains, where Bip acts to repress their activities. When cells are under stress, Bip dissociates from the initiator proteins. The dissociation relieves the repression and allows activation of these initiator proteins. Whereas UPR is activated to protect cells, it becomes destructive when ER stress is sustained. With excess ER stress, all three initiator proteins mediate signaling pathways to induce the expression of C/EBP homologous protein (CHOP), also known as growth arrest- and DNA damage-inducible gene 153 (GADD153), which promotes apoptotic cell death (Tabas and Ron, 2002, Szegezdi et al., 2006, Kim et al., 2008). Recently, it has shown that ER stress promotes catalytic activity of DAPK. Furthermore, DAPK plays a critical role in ER stress signaling, transmitting stress signals to two distinct directions, caspase activation and autophagy, and leading to cell death (Gozuacik et al., 2008). Bim is a Bcl-2 homology-3 (BH-3) only pro-apoptotic Bcl-2 family member. Alternative splicing of Bim mRNA results in three isoforms: BimEL, BimL and BimS (O’Connor et al., 1998). Cells with low level of Bim expression are resistant to death induction, and Bim overexpression sensitizes cells to death signals (Leung et al., 2008). Bim has also been found mediating ER stress caused cell death (Puthalakath et al., 2007). Bim expression is regulated by several kinase signal transduction pathways. Extracellular signal-regulated protein kinase1/2 (ERK1/2) fosters BimEL degradation via phosphorylation on Ser65 (Ser69 in human) (Ewings et al., 2007). In contrast, c-Jun-N-terminal kinase (JNK) has been associated with Bim up-regulation. Treatment of human lung adenocarcinoma ASTC-a-1 cells with ultraviolet (UV) irradiation results in increase of Bim expression by activation of JNK1/2–Foxo3a signal transduction pathway (Wang et al., 2012). Interestingly, enhanced Bim expression by Foxo3a also results in apoptotic cell death in neurons (Gilley et al., 2003).