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

Neurobiology of Aging
Mengjuan WuXiao-Chuan Wang

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.

Citations

Jan 10, 2021·Life Sciences·Liting YuChangying Guo
May 23, 2021·In Vitro Cellular & Developmental Biology. Animal·Valentina V NenashevaVyacheslav Z Tarantul

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