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.