Cell cycle events mediate lactacystin-induced apoptotic death of neuronal PC12 cells.
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.
Zhang
Zhentao
Z
Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Peoples Republic of China.
Xu
Yan
Y
Qin
Kairong
K
Wang
Tao
T
Cao
Xuebing
X
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000378:metabolism / Q000502:physiology; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D005419:Flavonoids / Q000494:pharmacology; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D016716:PC12 Cells; D051381:Rats
D018797:Cell Cycle Proteins; D015853:Cysteine Proteinase Inhibitors; D004791:Enzyme Inhibitors; D005419:Flavonoids; C067713:lactacystin; D048049:Extracellular Signal-Regulated MAP Kinases; D048052:Mitogen-Activated Protein Kinase 3; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D000111:Acetylcysteine