Ser46 phosphorylation of p53 is an essential event in prolyl-isomerase Pin1-mediated p53-independent apoptosis in response to heat stress

Ser46 phosphorylation of p53 is an essential event in prolyl-isomerase Pin1-mediated p53-independent apoptosis in response to heat stress

Abstract

Heat stroke has increased in frequency worldwide in recent years and continues to have a high morbidity and mortality. Identification of the mechanisms mediating heat stoke is important and necessary. Our preliminary study revealed heat stress (HS)-induced apoptosis of vascular endothelial cells was associated with reactive oxygen species (ROS)-induced p53 translocation into mitochondria. Previous studies have suggested the prolyl-isomerase Pin1 regulates p53 functioning through specific binding to p53 phosphorylation sites. Based on these studies, we presumed Pin1 is a key intermediate in regulation of mitochondrial p53 translocation through a HS-induced ROS-p53 transcription-independent apoptosis pathway. In this context, we revealed p53 had a crucial role in a HS-induced mitochondrial apoptotic pathway, where p53 protein rapidly translocated into mitochondria in endothelial cells both in vitro and in vivo. In particular, HS caused an increase in p53 phosphorylation at Ser46 that facilitated interactions with phosphorylation-dependent prolyl-isomerase Pin1, which has a key role in promoting HS-induced localization of p53 to mitochondria. Furthermore, we also found ROS production was a critical mediator in HS-induced Pin1/p53 signaling and was involved in regulating mitochondrial apoptosis pathway activation. Therefore, we have contributed to our profound understanding of the mechanism underlying HS-induced endothelial dysfunction in an effort to reduce the mortality and morbidity of heat stroke.

Authors: Li Li, Zijun Su, Zhimin Zou, Hongping Tan, Daozhang Cai, Lei Su & Zhengtao Gu

Influence Factor: 5.638

Citation: Cell Death Dis 10, 96 (2019).

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