title: Valproic acid downregulates Cdk5 activity via the transcription of the p35 mRNA.
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.
authors.affiliation: Department of Biological Sciences, Tokyo Metropolitan University, Hachioji, Tokyo 192-0397, Japan.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: Department of Biological Sciences, Tokyo Metropolitan University, Hachioji, Tokyo 192-0397, Japan.
authors.forename: Manami
authors.initials: M
authors.lastname: Ishida
authors.affiliation: Department of Biological Sciences, Tokyo Metropolitan University, Hachioji, Tokyo 192-0397, Japan.
authors.forename: Taro
authors.initials: T
authors.lastname: Saito
authors.affiliation: Department of Life Science and Medical Bio-Science, Waseda University, Shinjuku, Tokyo 162-8480, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Ohshima
authors.affiliation: Department of Biological Sciences, Tokyo Metropolitan University, Hachioji, Tokyo 192-0397, Japan. Electronic address: hisanaga-shinichi@tmu.ac.jp.
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Hisanaga
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D002491:Central Nervous System Agents / Q000494:pharmacology; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010770:Phosphotransferases / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: C492236:Cdk5r1 protein, mouse; D002491:Central Nervous System Agents; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D056572:Histone Deacetylase Inhibitors; D012333:RNA, Messenger; D014635:Valproic Acid; D010770:Phosphotransferases; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse
keywords: Autism; Cdk5; HDAC; Transcription; Valproic acid; p35