However, SIK2 levels were markedly reduced after OGD in parallel

However, SIK2 levels were markedly reduced after OGD in parallel with the increase in CRE activity and TORC1 dephosphorylation and nuclear translocation. AMPK and SIK1 did not exhibit such temporal associations with TORC1 and CRE activity. These observations raised the possibility that SIK2 regulates CREB-dependent transcription through an effect on TORC1 phosphorylation and nuclear translocation. Consistent with this

hypothesis, Bcr-Abl inhibitor overexpression of a constitutively active SIK2 suppressed OGD-induced CRE activity and increased cell death, whereas an inactive SIK2 was neuroprotective. Similarly, RNAi downregulation or pharmacological inhibition of SIK2 increased CRE activity and neuronal survival. The demonstration that SIK2 overexpression reduced CRE activity in cells cotransfected with a wild-type (WT) TORC1 construct, but was unable to do so in the presence of a phosphorylation-resistant mutant of TORC1, clearly established that these effects of SIK2 were mediated by TORC1 phosphorylation. Next, the authors set out to investigate the upstream

mechanisms by which OGD Cell Cycle inhibitor modulates SIK2 levels and CREB transcriptional activity. After identifying CaMK I/IV as potential upstream mediators of TORC1-CREB activation, the authors explored how CaMK I/IV activity could lead to the reduction in SIK2 levels induced by OGD. They found that overexpression of dominant-negative CaMK I or CaMK IV constructs prevents the OGD-induced downregulation of SIK2. Ribonucleotide reductase In addition, SIK2 degradation was associated with an increase in the phosphorylation of a specific SIK2 residue (Thr484). The importance of this site for SIK2 degradation was demonstrated by the fact that a phosphorylation-resistant Thr484 did not result in SIK2 degradation. In contrast, phosphorylation of Ser587, a SIK2 site also known to negatively regulate TORC phosphorylation (Katoh et al., 2006), did not impact SIK2 protein levels. In support of this conclusion,

OGD increased SIK2 Thr484 phosphorylation, but not Ser587 phosphorylation, suggesting that Thr484, but not Ser587, is an important target of CaMK I/IV-dependent SIK2 degradation. Sasaki et al. (2011) provide further support that SIK2 is a principal regulator of neuronal survival by generating sik2−/− mice and investigating whether neurons from these mice are protected from OGD. They found that sik2−/− neurons display higher survival rates than WT following OGD, an effect associated with a concomitant increase in TORC1-CREB activity and induction of prosurvival genes such as Bdnf and Ppargc-1a. Importantly, to determine whether SIK2 is involved in the mechanisms of neuronal death in vivo, they examined ischemic lesions in WT and sik2−/− mice following occlusion of the middle cerebral artery, a well-established model of ischemic stroke.

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