Activation of PKR promotes the nucleocytoplasmic export of p53

Abstract

Wild type p53 accumulates in the nucleus upon different types of stress. We previously reported that ER stress downregulates p53. ER stress inhibits protein synthesis by inducing the phosphorylation of eIF2α. The eIF2α kinase PKR plays a major role in the antiviral response. We have shown that PKR activation can also be induced upon ER stress. Our goal was to understand the molecular mechanisms of p53 downregulation by PKR by means that induce eIF2α phosphorylation such as virus infection and pharmacological inducers of ER stress. We report that PKR activation upon ER stress or dsRNA promotes p53 downregulation. This decrease in p53 protein levels was independent on the eIF2α-mediated translational inhibition properties of PKR. We observe that PKR mediates the nuclear export of p53 while promoting its degradation through the 26S proteasome pathway. This downregulation of p53 can be rescued by inhibiting the protein degradation pathway with MG132, as well as the prevention of p53 nuclear export with leptomycin B (LMB) despite the robust activation of PKR and eIF2α phosphorylation. This study provides evidence that PKR plays a role other than the inhibition of protein synthesis. This could explain how some cancer cells, bearing wild type p53, that overexpress PKR may overcome the tumor suppressor effects of p53 by inducing its nuclear export and degradation. This work was supported by NCIC.