Cell cycle events mediate lactacystin-induced apoptotic death of neuronal PC12 cells

Cell Biol Int. 2010 Dec;34(12):1181-7. doi: 10.1042/CBI20090079.

Abstract

Dysfunction of the UPS (ubiquitin-proteasome system) has been implicated in dopaminergic neuronal death in PD (Parkinson's disease). Recent studies suggest that unregulated cell cycle events play a key role in neuronal death. In this study, the effects of UPS dysfunction on cell cycle events in neuronal differentiated PC12 cells were analysed using a specific inhibitor of proteasome, lactacystin. Lactacystin induced apoptosis, G₂/M cell cycle arrest and sustained the phosphorylation of the pRB (retinoblastoma protein), the key molecular process of G₁/S transition, in neuronal PC12 cells. Furthermore, inhibition of cell cycle progression protected against lactacystin-induced cell apoptosis. Finally, we determined that lactacystin activated the ERK signalling pathway. Inhibition of ERK1/2 activation by MEK-1 inhibitor PD98059 decreased cell cycle aberrant and prevented apoptosis induced by lactacystin. These results indicate that aberrant cell cycle events contribute to apoptotic death induced by UPS dysfunction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcysteine / analogs & derivatives*
  • Acetylcysteine / pharmacology
  • Animals
  • Apoptosis / drug effects*
  • Cell Cycle / drug effects
  • Cell Cycle / physiology*
  • Cell Cycle Proteins / metabolism
  • Cell Cycle Proteins / physiology
  • Cell Death / drug effects
  • Cell Differentiation / drug effects
  • Cysteine Proteinase Inhibitors / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Extracellular Signal-Regulated MAP Kinases / physiology
  • Flavonoids / pharmacology
  • Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Mitogen-Activated Protein Kinase 3 / physiology
  • Neurons / drug effects*
  • Neurons / pathology
  • PC12 Cells
  • Rats

Substances

  • Cell Cycle Proteins
  • Cysteine Proteinase Inhibitors
  • Enzyme Inhibitors
  • Flavonoids
  • lactacystin
  • Extracellular Signal-Regulated MAP Kinases
  • Mitogen-Activated Protein Kinase 3
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
  • Acetylcysteine