SIK2 Is a Key Regulator for Neuronal Survival after Ischemia via TORC1-CREB

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• 作者：Tsutomu Sasaki¹ ; Hiroshi Takemori² ; ^{takemori@nibio.go.jp} ; Yoshiki Yagita¹ ; Yasukazu Terasaki¹ ; Tatsuya Uebi² ; Nanao Horike² ; Hiroaki Takagi³ ; Teruo Susumu³ ; Hiroshi Teraoka³ ; Ken-ichi Kusano³ ; Osamu Hatano⁴ ; Naoki Oyama¹ ; Yukio Sugiyama¹ ; Saburo Sakoda¹ ; Kazuo Kitagawa¹ ; ^{kitagawa@medone.med.osaka-u.ac.jp}
• 刊名：Neuron
• 出版年：2011
• 出版时间：13 January 2011
• 年：2011
• 卷：69
• 期：1
• 页码：106-119
• 全文大小：1980 K

文摘

Summary

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. Ca²⁺/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.