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

Authors

  • Zhentao Zhang,

    Corresponding author
    1. Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Peoples Republic of China
    2. Department of Neurology, Renmin Hospital of Wuhan University, Wuhan 430060, Peoples Republic of China
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  • Yan Xu,

    Corresponding author
    1. Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Peoples Republic of China
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  • Kairong Qin,

    1. Department of Medical Rehabilitation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Peoples Republic of China
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  • Tao Wang,

    1. Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Peoples Republic of China
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  • Xuebing Cao

    Corresponding author
    1. Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Peoples Republic of China
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Zhentao Zhang and Yan Xu contributed equally to this work.

To whom correspondence should be addressed (email caoxuebing@126.com).

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.

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