Dicer protein levels elevated by mild hyperthermia promote a pro-survival phenotype

Abstract

Cellular exposure to mild stress (39.5°C - 41.5°C) induces thermotolerance, rendering cells resistant to a subsequent heat shock (>42°C) insult. We found that mild hyperthermia at 39.5°C leads to elevations in dicer, a protein well-known for its role in microRNA processing and for its role in cellular stress responses. However, whether elevated dicer protein levels play a role in sustaining a thermotolerant phenotype has, to our knowledge, not been reported. Here we demonstrate that elevated dicer protein is linked to a thermotolerant phenotype in the cervical carcinoma cell line HeLa and in murine embryonic fibroblasts (MEF), and demonstrate that dicer plays a role in mediating PKR and eIF2α phosphorylation. These findings suggest that dicer's role in thermotolerance may be to relay signals to key ER stress pathway components. Moreover, utilizing a MEF cell line defective in microRNA processing, we suggest that dicer's influence on PKR and eIF2α phosphorylation is likely distinct from its microRNA processing role. ATF4 and CHOP are well characterized stress response factors proximal to eIF2α. Evidence is presented that elevated dicer protein in thermotolerant cells differentially modulates ATF4 and CHOP levels to promote a pro-survival phenotype. This work contributes new information on dicer's role in cellular stress responses by defining a pro-survival phenotype in heat stress resistant cells which is sustained, at least in part, by elevated dicer protein levels. Our results suggest an ancillary role for dicer in the cellular stress pathways activated by mild hyperthermia that is likely distinct from its role in microRNA processing.

Cellular Response to ELF-MF and Heat: Evidence for a Common Involvement of Heat Shock Proteins?

“…This is reflected in both the gene expression pattern ( 8 , 9 ) and the physiological responses within the cell ( 10 ). In addition, there is evidence that pretreatment with a mild heat stress significantly improves the resilience of the cell if it is later exposed to a high (lethal), temperature ( 11 – 13 ). Repeated mild heat stress has even been shown to stimulate proliferation and differentiation in human adipose tissue-derived mesenchymal stem cells ( 14 ).…”

Cold water immersion in recovery following a single bout resistance exercise suppresses mechanisms of miRNA nuclear export and maturation

“…Transient hypothermia and hyperthermia both exert a pronounced influence on miRNA abundances and their transcriptional activity in multiple tissue and cell types (Chen et al, 2018 ; Fukuoka et al, 2014 ; Liu et al, 2017 ; Umehara et al, 2020 ). More specifically to exercise, in long‐distance runners who experienced hypothermia there was differential regulation of muscle miRNA species compared to runners who did not experience hypothermia (Devasthanam & Tomasi, 2017 ; Umehara et al, 2020 ). Further, cell culture studies have identified that the DICER protein is highly sensitive to both hyperthermia and hypothermia (Pilotte et al, 2011 ).…”

“…Collectively, these findings provide a hypothetical basis for investigation of the impact of CWI on the molecular mechanisms of miRNA regulation (DROSHA, EXPORTIN‐5, and DICER) and expression of specific miRNA species related to exercise adaptations in response to CWI during exercise recovery (Peake et al, 2020 ). On the basis of prior cell culture studies (Devasthanam & Tomasi, 2017 ), we hypothesized that CWI would elevate muscle DICER expression following a single bout of resistance exercise. Further analysis was conducted to quantify various miRNA species previously implicated in the adaptive response to muscle loading including intracellular anabolic signaling (miR‐1 and miR‐133a; McCarthy & Esser, 2007 ) and angiogenesis (miR‐15a and miR‐126a; Fish et al, 2008 ; Sun et al, 2013 ; Wang et al, 2016 ; Yin et al, 2012 ).…”

MicroRNAs Regulating Cytoskeleton Dynamics, Endocytosis, and Cell Motility—A Link Between Neurodegeneration and Cancer?

“…Mutations in DICER1 gene and reduced Dicer activity are associated with increased susceptibility to stress, apoptosis, developmental abnormalities, aging, metabolic disorders, disturbed immune system and neuronal functions, and neurodegeneration ( 29 , 32 – 48 ). Conversely, increased Dicer levels and/or activity are mostly associated with increased cell survival, but also tumorigenesis ( 6 , 49 – 52 ).…”