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p53-mediated control of gene expression via mRNA translation during Endoplasmic Reticulum stress
Ignacio López1, Anne-Sophie Tournillon1, Karin Nylander2
1a Équipe Labellisée Ligue Contre le Cancer; Université Paris 7; INSERM UMR 1162 "Génomique fonctionnelle des tumeurs solides" ; Paris , France
Abstract:
p53 is activated by different stress and damage pathways and regulates cell biological responses including cell cycle arrest, repair pathways, apoptosis and senescence. Following DNA damage, the levels of p53 increase and via binding to target gene promoters, p53 induces expression of multiple genes including p21(CDKN1A) and mdm2. The effects of p53 on gene expression during the DNA damage response are well mimicked by overexpressing p53 under normal conditions. However, stress to the Endoplasmic Reticulum (ER) and the consequent Unfolded Protein Response (UPR) leads to the induction of the p53/47 isoform that lacks the first 40 aa of p53 and to an active suppression of p21(CDKN1A) transcription and mRNA translation. We now show that during ER stress p53 also suppresses MDM2 protein levels via a similar mechanism. These observations not only raise questions about the physiological role of MDM2 during ER stress but it also reveals a new facet of p53 as a repressor toward 2 of its major target genes during the UPR. As suppression of p21(CDKN1A) and MDM2 protein synthesis is mediated via their coding sequences, it raises the possibility that p53 controls mRNA translation via a common mechanism that might play an important role in how p53 regulates gene expression during the UPR, as compared to the transcription-dependent gene regulation taking place during the DNA damage response.
Insights
The tumor suppressor p53, normally promoting gene expression after DNA damage, actively suppresses protein synthesis of p21 and MDM2 during Endoplasmic Reticulum stress. This reveals a new repressive role for p53 in the Unfolded Protein Response.
Area of Science:
- Molecular Biology
- Cellular Stress Response
- Cancer Biology
Background:
- The p53 protein is a critical tumor suppressor activated by various cellular stresses, including DNA damage.
- Upon DNA damage, p53 typically induces target genes like p21(CDKN1A) and MDM2, promoting cell cycle arrest and repair.
- Endoplasmic Reticulum (ER) stress triggers the Unfolded Protein Response (UPR), which involves distinct p53 regulatory mechanisms.
Purpose of the Study:
- To investigate the role of p53 during Endoplasmic Reticulum (ER) stress and the Unfolded Protein Response (UPR).
- To determine how p53 regulates its target genes, p21(CDKN1A) and MDM2, under ER stress conditions.
- To explore a potential new mechanism of p53-mediated gene regulation involving mRNA translation.
Main Methods:
- Overexpression of p53 under normal and ER stress conditions.
- Analysis of p21(CDKN1A) and MDM2 transcription and translation levels.
- Investigation of p53 isoform activity during the UPR.
Main Results:
- ER stress induces a p53 isoform (p53/47) lacking the N-terminal 40 amino acids.
- This p53 isoform actively suppresses both p21(CDKN1A) and MDM2 transcription and translation.
- Suppression of p21(CDKN1A) and MDM2 occurs via their coding sequences, suggesting translational control.
Conclusions:
- p53 acts as a repressor of key target genes, p21(CDKN1A) and MDM2, during the UPR.
- This repressive function appears to be mediated through mRNA translation, distinct from its transcriptional role in DNA damage response.
- These findings reveal a novel facet of p53 regulation and its role in cellular stress management during ER stress.
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