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.

Lessons From Heat Stroke for Understanding Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

“…ATP depletion ( 36 ) as well mitochondrial swelling and vacuolization in the epithelial cells of the gut have been observed in the mice models of heat stroke ( 52 ). Moreover, animal studies have shown that apoptosis of vascular endothelial cells in heat stroke was the deleterious consequence of reactive oxygen species (ROS)-induced p53 translocation into mitochondria ( 133 ). Finally, it was shown in vitro that higher temperatures can directly affect the viscosity of mitochondria ( 134 ).…”

Cell Fate Regulation upon DNA Damage: p53 Serine 46 Kinases Pave the Cell Death Road

“…To date, five proline‐directed Ser/Thr kinases have been proposed to catalyze p53 Ser46 phosphorylation in response to DNA‐damaging such as IR, UV, and treatment with chemotherapeutic agents such as Adriamycin, Cisplatin, and Temozolomide, namely HIPK2, ATM, DYRK2, p38α, and PKCδ ( Figure ). Although p53 Ser46 phosphorylation has been most abundantly studied upon genotoxic stress, the Ser46 phospho‐mark has also been observed in response to heat shock and energy stress by glucose deprivation and AMPKα activation, suggesting an even broader function in cytotoxic stress‐mediated cell death responses (Figure ). In the following paragraphs, we will summarize the current evidence linking these kinases to p53 Ser46 phosphorylation and we will highlight the mechanisms by which the Ser46 kinases are wired to the damage‐induced signaling network.…”

Compatibility of ingredients of Danshen (Radix Salviae Miltiorrhizae) and Honghua (Flos Carthami) and their protective effects on cerebral ischemia‑reperfusion injury in rats

“…The caspase family serves an important role in the apoptotic process of neurons ( 47 , 48 ). This family of proteins represents the common pathway for the final implementation of apoptosis ( 49 ).…”