title: SIK2 is a key regulator for neuronal survival after ischemia via TORC1-CREB.
abstract: The cAMP responsive element-binding protein (CREB) functions in a broad array of biological and pathophysiological processes. We found that salt-inducible kinase 2 (SIK2) was abundantly expressed in neurons and suppressed CREB-mediated gene expression after oxygen-glucose deprivation (OGD). OGD induced the degradation of SIK2 protein concomitantly with the dephosphorylation of the CREB-specific coactivator transducer of regulated CREB activity 1 (TORC1), resulting in the activation of CREB and its downstream gene targets. Ca(2+)/calmodulin-dependent protein kinase I/IV are capable of phosphorylating SIK2 at Thr484, resulting in SIK2 degradation in cortical neurons. Neuronal survival after OGD was significantly increased in neurons isolated from sik2(-/-) mice, and ischemic neuronal injury was significantly reduced in the brains of sik2(-)(/-) mice subjected to transient focal ischemia. These findings suggest that SIK2 plays critical roles in neuronal survival, is modulated by CaMK I/IV, and regulates CREB via TORC1.
authors.affiliation: Department of Neurology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Sasaki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takemori
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Yagita
authors.forename: Yasukazu
authors.initials: Y
authors.lastname: Terasaki
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Uebi
authors.forename: Nanao
authors.initials: N
authors.lastname: Horike
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Takagi
authors.forename: Teruo
authors.initials: T
authors.lastname: Susumu
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Teraoka
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Kusano
authors.forename: Osamu
authors.initials: O
authors.lastname: Hatano
authors.forename: Naoki
authors.initials: N
authors.lastname: Oyama
authors.forename: Yukio
authors.initials: Y
authors.lastname: Sugiyama
authors.forename: Saburo
authors.initials: S
authors.lastname: Sakoda
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kitagawa
mesh_terms: D000818:Animals; D050882:CREB-Binding Protein / Q000378:metabolism*; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1 / Q000378:metabolism; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4 / Q000378:metabolism; D002452:Cell Count; D015687:Cell Hypoxia; D002470:Cell Survival; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004274:DNA, Recombinant; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs; D009474:Neurons / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: C519509:Crtc1 protein, mouse; D004274:DNA, Recombinant; D035683:MicroRNAs; D014157:Transcription Factors; D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse; C474808:salt-inducible kinase-2, mouse; D017346:Protein Serine-Threonine Kinases; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D005947:Glucose; D010100:Oxygen