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p53-mediated control of gene expression via mRNA translation during Endoplasmic Reticulum stress
Umeå University, Faculty of Medicine, Department of Medical Biosciences.
Umeå University, Faculty of Medicine, Department of Medical Biosciences. Univ Paris 07, Equipe Labellisee Ligue Canc, Paris, France; INSERM, UMR Genom Fonct Tumeurs Solides 1162, Paris, France; Masaryk Mem Canc Inst, RECAMO, Brno, Czech Republic.
2015 (English)In: Cell Cycle, ISSN 1538-4101, E-ISSN 1551-4005, Vol. 14, no 21, 3373-3378 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2015. Vol. 14, no 21, 3373-3378 p.
Keyword [en]
ER stress, MDM2, mRNA translation, p53, 47
National Category
Cell Biology
URN: urn:nbn:se:umu:diva-112251DOI: 10.1080/15384101.2015.1090066ISI: 000364559400011PubMedID: 26397130OAI: diva2:878189
Available from: 2015-12-08 Created: 2015-12-04 Last updated: 2015-12-08Bibliographically approved

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