Gadd45a, the Gene Induced by the Mood Stabilizer Valproic Acid, Regulates Neurite Outgrowth Through JNK and the Substrate Paxillin in N1E-115 Neuroblastoma Cells

Exp Cell Res. 2007 May 15;313(9):1886-96. doi: 10.1016/j.yexcr.2007.02.019. Epub 2007 Feb 28.

Abstract

Valproic acid (VPA), a mood stabilizer and anticonvulsant, has a variety of neurotrophic functions; however, less is known about how VPA regulates neurite outgrowth. Here, using N1E-115 neuroblastoma cells as the model, we show that VPA upregulates Gadd45a to trigger activation of the downstream JNK cascade controlling neurite outgrowth. VPA induces the phosphorylation of c-Jun N-terminal kinase (JNK) and the substrate paxillin, while VPA induction of neurite outgrowth is inhibited by JNK inhibitors (SP600125 and the small JNK-binding peptide) or a paxillin construct harboring a Ser 178-to-Ala mutation at the JNK phosphorylation. Transfection of Gadd45a, acting through the effector MEKK4, leads to the phosphorylation of the JNK cascade. Conversely, knockdown of Gadd45a with siRNA reduces the effect of VPA. Taken together, these results suggest that upregulation of Gadd45a explains one of the mechanisms whereby VPA induces the neurotrophic effect, providing a new role of Gadd45a in neurite outgrowth.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimanic Agents / pharmacology
  • Cell Cycle Proteins / drug effects
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Differentiation / drug effects
  • Cell Differentiation / physiology*
  • Down-Regulation / genetics
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology
  • JNK Mitogen-Activated Protein Kinases / drug effects
  • JNK Mitogen-Activated Protein Kinases / metabolism*
  • MAP Kinase Kinase Kinase 4 / drug effects
  • MAP Kinase Kinase Kinase 4 / metabolism
  • Mice
  • Nerve Growth Factors / pharmacology
  • Neurites / drug effects
  • Neurites / metabolism
  • Neuroblastoma
  • Neurons / drug effects
  • Neurons / metabolism*
  • Neuroprotective Agents / pharmacology
  • Nuclear Proteins / drug effects
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Paxillin / drug effects
  • Paxillin / genetics
  • Paxillin / metabolism*
  • Phosphorylation / drug effects
  • RNA Interference / physiology
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Up-Regulation / drug effects
  • Up-Regulation / physiology
  • Valproic Acid / pharmacology*

Substances

  • Antimanic Agents
  • Cell Cycle Proteins
  • Enzyme Inhibitors
  • Gadd45a protein, mouse
  • Nerve Growth Factors
  • Neuroprotective Agents
  • Nuclear Proteins
  • Paxillin
  • Valproic Acid
  • JNK Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 4
  • Map3k4 protein, mouse