Inactivation of HDAC5 by SIK1 in AICAR-treated C2C12 myoblasts

Hiroshi Takemori, Yoshiko Katoh Hashimoto, Jun Nakae, Eric N. Olson, Mitsuhiro Okamoto

Research output: Contribution to journalArticlepeer-review

46 Scopus citations


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 Thrl82. The activated SIK1 then auto-phosphorylates its Serl86 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)-lα gene expression. However, expression of the PGC-lα gene has been found to be repressed in LKB1 -defective muscle cells. Our findings show that the AMPK agonist 5-aminoimidazole-4-carboxamide-l-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-3P enzyme purified from AICAR-treated cells shows enhanced phosphorylation activity of SIK1 in vitro. These observations suggest that GSK-3β and SIK1 may play important roles in the regulation of PGC-1α gene expression by inactivating HDAC5 followed by activation of MEF2C.

Original languageEnglish (US)
Pages (from-to)121-130
Number of pages10
JournalEndocrine Journal
Issue number1
StatePublished - 2009


  • AMPK
  • C2C12 cells
  • HDAC5
  • SIK1

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology


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