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Neurobiol Aging. 2018 Sep;69:38-47. doi: 10.1016/j.neurobiolaging.2018.04.022. Epub 2018 May 8.

Phosphorylation of SET mediates apoptosis via P53 hyperactivation and NM23-H1 nuclear import.

Author information

1
Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
2
Experimental Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
3
Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China.
4
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
5
School of Public Health, Wuhan University of Science and Technology, Wuhan, China.
6
Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China. Electronic address: wxch@mails.tjmu.edu.cn.

Abstract

Apoptosis plays an important role in neuron loss in Alzheimer's disease (AD). SET, an endogenous inhibitor of protein phosphatase-2A, is phosphorylated in AD brains and positively correlates with cell apoptosis. However, the mechanism underlying phosphorylated SET association with apoptosis remains unknown. Here, we show that mimetic phosphorylation of SET (S9E) induced apoptosis of primary cultured neurons. To investigate its mechanism, we overexpressed SET (S9E) in HEK293/tau cells and observed apoptosis accompanied with a marked increase of cleaved caspase-3 and cytoplasmic SET (S9E) retention with enhanced protein phosphatase-2A inhibition, which subsequently caused p53 hyperphosphorylation and activation. In addition, it caused the release of nucleoside diphosphate kinase A isoform a, a positive regulator of p53 with a DNase activity from SET/nucleoside diphosphate kinase A isoform a complex, and migration into the nucleus, resulting in DNA damage. Besides, it reduced nuclear tau accumulation leading to DNA protection deficiency. These findings suggest that SET phosphorylation is involved in the neuronal apoptotic pathway in AD and provide a new insight into the mechanism of this pathology.

KEYWORDS:

Alzheimer's disease; Apoptosis; NM23-H1; SET; Tau; p53

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