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 journalArticle

40 Citations (Scopus)

Abstract

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
Volume56
Issue number1
DOIs
StatePublished - 2009

Fingerprint

Aminoimidazole Carboxamide
AMP-Activated Protein Kinases
Myoblasts
Glycogen Synthase Kinase 3
Cyclic AMP Response Element-Binding Protein
Phosphorylation
Transcription Factors
Gene Expression
Glycogen Synthase Kinases
Peroxisome Proliferator-Activated Receptors
Histone Deacetylases
Cell Nucleus Active Transport
Transducers
Muscle Cells
Phosphotransferases
Up-Regulation
Salts
4-aminoimidazole
Liver
Enzymes

Keywords

  • AICAR
  • AMPK
  • C2C12 cells
  • HDAC5
  • SIK1

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

Inactivation of HDAC5 by SIK1 in AICAR-treated C2C12 myoblasts. / Takemori, Hiroshi; Hashimoto, Yoshiko Katoh; Nakae, Jun; Olson, Eric N.; Okamoto, Mitsuhiro.

In: Endocrine Journal, Vol. 56, No. 1, 2009, p. 121-130.

Research output: Contribution to journalArticle

Takemori, H, Hashimoto, YK, Nakae, J, Olson, EN & Okamoto, M 2009, 'Inactivation of HDAC5 by SIK1 in AICAR-treated C2C12 myoblasts', Endocrine Journal, vol. 56, no. 1, pp. 121-130. https://doi.org/10.1507/endocrj.K08E-173
Takemori, Hiroshi ; Hashimoto, Yoshiko Katoh ; Nakae, Jun ; Olson, Eric N. ; Okamoto, Mitsuhiro. / Inactivation of HDAC5 by SIK1 in AICAR-treated C2C12 myoblasts. In: Endocrine Journal. 2009 ; Vol. 56, No. 1. pp. 121-130.
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