Activation of PKR promotes the nucleocytoplasmic export of p53
Bibliographic record
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.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".