Inactivation of HDAC5 by SIK1 in AICAR-treated C2C12 Myoblasts

Endocrine Journal

Mitsuhiro OKAMOTO⁴  Hiroshi TAKEMORI¹  Jun NAKAE²  Yoshiko KATOH HASHIMOTO¹  Eric N. OLSON³ 

[1] Laboratory of Cell Signaling and Metabolism, National Institute of Biomedical Innovation;Department of Clinical Molecular Medicine, Division of Diabetes, Digestive and Kidney Disease, Kobe University Graduate School of Medicine;Department of Molecular Biology, University of Texas Southwestern Medical Center;Faculty of Contemporary Human Life Science, Tezukayama University

关键词: SIK1;    HDAC5;    AICAR;    AMPK;    C2C12 cells;   

DOI  :  10.1507/endocrj.K08E-173

学科分类：内分泌与代谢学

来源: Japan Endocrine Society

【 摘 要 】

References(44)Cited-By(16)Salt inducible kinase (SIK) 1, a member of the AMP-activated kinase (AMPK) family, is activated by the AMPK-activator LKB1 which phosphorylates SIK1 at Thr182. The activated SIK1 then auto-phosphorylates its Ser186 located at the +4 position of Thr182. The phospho-Ser186 is essential for sustained activity of SIK1, which is maintained by sequential phosphorylation at Ser186-Thr182 by glycogen synthase kinase (GSK)-3β. Meanwhile, SIK1 represses the transcription factor cAMP-response element binding protein (CREB) by phosphorylating its co-activator transducer of regulated CREB activity (TORC). Recently, histone deacetylase (HDAC) 5 was identified as a new substrate of SIK1. Inhibition of SIK1 or AMPK results in the stimulation of glyconeogensis in the liver by enhancing dephosphorylation of TORC2 followed by up-regulation of peroxisome proliferator-activated receptor coactivator (PGC)-1α gene expression. However, expression of the PGC-1α gene has been found to be repressed in LKB1-defective muscle cells. Our findings show that the AMPK agonist 5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside (AICAR)-dependent expression of PGC-1α is diminished by inhibitors of GSK-3β or SIKs in C2C12 myoblasts. Treatment with AICAR or the overexpression of SIK1 induces nuclear export of HDAC5 followed by the activation of myogenic transcription factor (MEF)-2C. The levels of phosphorylation at Thr182 and Ser186 of SIK1 in AICAR-treated C2C12 cells are elevated, and GSK-3β enzyme purified from AICAR-treated cells shows enhanced phosphorylation activity of SIK1 in vitro. These observations suggest that GSK-3 β and SIK1 may play important roles in the regulation of PGC-1α gene expression by inactivating HDAC5 followed by activation of MEF2C.

【 授权许可】

Unknown