Valproic acid downregulates Cdk5 activity via the transcription of the p35 mRNA

Miyuki Takahashi, Manami Ishida, Taro Saito, Toshio Ohshima, Shin Ichi Hisanaga

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

The cyclin-dependent kinase 5 (Cdk5) is a neuron-specific Ser/Thr kinase that is activated by the regulatory subunit p35. Overactivation of Cdk5, which is induced by the cleavage of p35 by calpain, is implicated in neuronal death in various neurodegenerative diseases. In contrast, depletion of the Cdk5 activity renders neurons vulnerable to stresses. Recent reports suggest the involvement of Cdk5 in mental disorders. We hypothesized that perturbation of Cdk5 activity is related to mental conditions. To verify this hypothesis, we investigated the effect of valproic acid (VPA), which is a drug of choice for psychiatric disorders, on Cdk5 activity. VPA decreased the expression of p35 at both the protein and mRNA levels in cultured neurons, resulting in a decrease of Cdk5 activity. VPA decreased the p35 mRNA via histone deacetylase inhibition. The chronic administration of VPA also downregulated p35 in mouse brains. These results indicate that VPA regulates Cdk5 activity in neurons via p35 transcription mediated by HDAC inhibition.

Original languageEnglish
Pages (from-to)678-682
Number of pages5
JournalBiochemical and Biophysical Research Communications
Volume447
Issue number4
DOIs
Publication statusPublished - 2014 May 16

Keywords

  • Autism
  • Cdk5
  • HDAC
  • Transcription
  • Valproic acid
  • p35

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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