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p53-mediated suppression of BiP triggers BIK-induced apoptosis during prolonged endoplasmic reticulum stress
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2017 (English)In: Cell Death and Differentiation, ISSN 1350-9047, E-ISSN 1476-5403, Vol. 24, no 10, p. 1717-1729Article in journal (Refereed) Published
Abstract [en]

Physiological and pathological conditions that affect the folding capacity of the endoplasmic reticulum (ER) provoke ER stress and trigger the unfolded protein response (UPR). The UPR aims to either restore the balance between newly synthesized and misfolded proteins or if the damage is severe, to trigger cell death. However, the molecular events underlying the switch between repair and cell death are not well understood. The ER-resident chaperone BiP governs the UPR by sensing misfolded proteins and thereby releasing and activating the three mediators of the UPR: PERK, IRE1 and ATF6. PERK promotes G2 cell cycle arrest and cellular repair by inducing the alternative translated p53 isoform p53.N40 (p53/47), which activates 14-3-3 sigma via suppression of p21(CDKN1A). Here we show that prolonged ER stress promotes apoptosis via a p53-dependent inhibition of BiP expression. This leads to the release of the pro-apoptotic BH3-only BIK from BiP and activation of apoptosis. Suppression of bip mRNA translation is mediated via the specific binding of p53 to the first 346-nt of the bip mRNA and via a p53 trans-suppression domain located within the first seven N-terminal amino acids of p53 Delta N40. This work shows how p53 targets BiP to promote apoptosis during severe ER stress and further illustrates how regulation of mRNA translation has a key role in p53-mediated regulation of gene expression during the UPR.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP , 2017. Vol. 24, no 10, p. 1717-1729
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Cell Biology
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URN: urn:nbn:se:umu:diva-140028DOI: 10.1038/cdd.2017.96ISI: 000410166300006PubMedID: 28622297OAI: oai:DiVA.org:umu-140028DiVA, id: diva2:1146253
Available from: 2017-10-02 Created: 2017-10-02 Last updated: 2018-06-09Bibliographically approved

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Nylander, KarinFåhraeus, Robin

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