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J Neurochem. 2015 Aug;134(4):668-76. doi: 10.1111/jnc.13172. Epub 2015 Jun 26.

Rotenone affects p53 transcriptional activity and apoptosis via targeting SIRT1 and H3K9 acetylation in SH-SY5Y cells.

Author information

1
Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
2
Shanghai Geriatric Institute of Chinese Medicine, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
3
Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, Texas, USA.
4
Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University, Xiamen, Fujian Province, China.
5
Sanford-Burnham Medical Research Institute, La Jolla, California, USA.

Abstract

The protein deacetylase SIRT1 has been recognized to exert its protective effect by directly deacetylasing histone and many other transcriptional factors including p53. However, the effect of SIRT1 on p53 expression at the transcriptional level still remains to be elucidated. In this study, we found that rotenone treatment decreased cell viability, induced apoptosis, reduced SIRT1 level, and promoted p53 expression. Pre-treatment with resveratrol, a SIRT1 activator, could attenuate rotenone-induced cell injury and p53 expression, whereas down-regulation of SIRT1 directly increased p53 expression. Moreover, chromatin immunoprecipitation experiments showed that SIRT1 bound to H3K9 within the p53 promoter region, and this binding resulted in decreased H3K9 acetylation and increased H3K9 tri-methylation, thereby inhibiting p53 gene transcription. In conclusion, our data indicate that rotenone promotes p53 transcription and apoptosis through targeting SIRT1 and H3K9. This leads to nigrostriatal degeneration, the main pathogenic mechanism of motor features of Parkinson's disease. SIRT1, a deacetylase enzyme, has neuroprotective effects for Parkinson's disease via targeting various factors. Resveratrol activated SIRT1 can target H3K9 and regulate p53 gene expression at the transcriptional level, thus inhibiting p53 transcription to enhance neuroprotection, alleviating rotenone induced dopaminergic neurodegeneration. We think these findings should provide a new strategy for the treatment of Parkinson's disease.

KEYWORDS:

H3K9-ac; H3K9-me3; SIRT1; p53; resveratrol

PMID:
25991017
DOI:
10.1111/jnc.13172
[Indexed for MEDLINE]
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