An insight into the mechanistic role of p53-mediated autophagy induction in response to proteasomal inhibition-induced neurotoxicity

Yunlan Du, Dehua Yang, Ang Li, Guangrui Luo, Ting Li, Xiaolan Fan, Qian Wang, Xin Zhang, Yi Wang, Weidong Le

Research output: Contribution to journalArticle

61 Scopus citations

Abstract

The ubiquitin-proteasome system (UPS) and the autophagylysosomal pathway (ALP) are the two most important components of cellular mechanisms for protein degradation. In the present study we investigated the functional relationship of the two systems and the interactional role of p53 in vitro. Our study showed that the proteasome inhibitor lactacystin induced an increase in p53 level and autophagy activity, whereas inhibition of p53 by pifithrin-α or small interference RNA (siRNA) of p53 attenuated the autophagy induction and increased protein aggregation. Furthermore, we found that pretreatment with the autophagy inhibitor 3-methyladenine or beclin 1 siRNA further activated p53 and its downstream apoptotic pathways, while the autophagy inducer rapamycin showed the opposite effects. Moreover, we demonstrated that rapamycin pretreatment increased tyrosine hydroxylase (TH) protein level in dopamine (DA) neurons, which was associated with its induction of autophagy to degrade aggregated proteins. Our results suggest that p53 can mediate proteasomal inhibition-induced autophagy enhancement which in turn can partially block p53 or its downstream mitochondria-dependent apoptotic pathways. Further autophagy induction with rapamycin protects DA neurons from lactacystin-mediated cell death by downregulating p53 and its related apoptotic pathways and by inducing autophagy to degrade aggregated proteins. Therefore, rapamycin may be a promising drug for protection against neuronal injury relevant to Parkinson disease (PD). Our studies thus provide a mechanistic insight into the functional link between the two protein degradation systems.

Original languageEnglish (US)
Pages (from-to)663-675
Number of pages13
JournalAutophagy
Volume5
Issue number5
DOIs
StatePublished - Jul 1 2009

Keywords

  • Autophagy
  • p53
  • Parkinson disease
  • Rapamycin
  • Ubiquitin-proteasome system

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

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