Endoplasmic Reticulum Stress Induces G2 Cell-Cycle Arrest via mRNA Translation of the p53 Isoform p53/47

Bourougaa, Karima; Naski, Nadia; Boularan, Cédric; Mlynarczyk, Coraline; Candeias, Marco M.; Marullo, Stéfano; Fåhræus, Robin

doi:10.1016/j.molcel.2010.01.041

Cited by 146 publications

(198 citation statements)

References 43 publications

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“…14-3-3σ was recently reported as a preferential Δ40p53 target gene. 5,14 Expressing Δ40p53 from the 14A-M2 plasmid resulted in a 70% increase in 14-3-3σ mRNA in H1299-NS cells (Figure 2e). However, SMAR1 knockdown greatly compromised the induction of 14-3-3σ mRNA with only about 17% increase in the H1299-S3 cells, suggesting that SMAR1 is required for Δ40p53-mediated transactivation ( Figure 2e).…”

Section: Resultsmentioning

confidence: 97%

“…37,38,[50][51][52][53][54] Our recent study showed that SMAR1 is directly linked to translation of both p53 and Δ40p53 in normal as well as glucose-deprived conditions.14-3-3σ was demonstrated as a preferential transcriptional target of Δ40p53. 5,14 The downstream effects of Δ40p53 induction on target gene activation, and the resulting biological outcome, have been previously explored. [55][56][57] In the current study, using Δ40p53-mediated transactivation as a model, we showed that SMAR1 is important for IRESdependent Δ40p53 induction, as well as for the consequent elevation of 14-3-3σ mRNA (Figure 2e).…”

Section: Discussionmentioning

confidence: 99%

“…1 p53 and its N-terminally truncated isoform Δ40p53 (also known as ΔN-p53 or p53/47) are translated by internal ribosome entry site (IRES)-mediated translation initiation from the same mRNA under different stress conditions that induce DNA damage, ionizing radiation and endoplasmic reticulum (ER) stress, oncogene-induced senescence and cancer. [2][3][4][5][6][7] Thus, p53 mRNA has a dual IRES structure. 8 For their function, these IRESs rely on IRES trans-acting factors (ITAFs).…”

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Reversible induction of translational isoforms of p53 in glucose deprivation

et al. 2015

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Tumor suppressor protein p53 is a master transcription regulator, indispensable for controlling several cellular pathways. Earlier work in our laboratory led to the identification of dual internal ribosome entry site (IRES) structure of p53 mRNA that regulates translation of full-length p53 and Δ40p53. IRES-mediated translation of both isoforms is enhanced under different stress conditions that induce DNA damage, ionizing radiation and endoplasmic reticulum stress, oncogene-induced senescence and cancer. In this study, we addressed nutrient-mediated translational regulation of p53 mRNA using glucose depletion. In cell lines, this nutrient-depletion stress relatively induced p53 IRES activities from bicistronic reporter constructs with concomitant increase in levels of p53 isoforms. Surprisingly, we found scaffold/matrix attachment region-binding protein 1 (SMAR1), a predominantly nuclear protein is abundant in the cytoplasm under glucose deprivation. Importantly under these conditions polypyrimidine-tractbinding protein, an established p53 ITAF did not show nuclear-cytoplasmic relocalization highlighting the novelty of SMAR1-mediated control in stress. In vivo studies in mice revealed starvation-induced increase in SMAR1, p53 and Δ40p53 levels that was reversible on dietary replenishment. SMAR1 associated with p53 IRES sequences ex vivo, with an increase in interaction on glucose starvation. RNAi-mediated-transient SMAR1 knockdown decreased p53 IRES activities in normal conditions and under glucose deprivation, this being reflected in changes in mRNAs in the p53 and Δ40p53 target genes involved in cell-cycle arrest, metabolism and apoptosis such as p21, TIGAR and Bax. This study provides a new physiological insight into the regulation of this critical tumor suppressor in nutrient starvation, also suggesting important functions of the p53 isoforms in these conditions as evident from the downstream transcriptional target activation. Cell Death and Differentiation (2015) 22, 1203-1218; doi:10.1038/cdd.2014.220; published online 27 February 2015 p53 is a master transcription factor and tumor suppressor. Apart from post-translational modifications of p53 and concomitant protein-protein interactions of p53 with diverse factors, translational control of p53 mRNA also plays an important role under stress conditions. 1 p53 and its N-terminally truncated isoform Δ40p53 (also known as ΔN-p53 or p53/47) are translated by internal ribosome entry site (IRES)-mediated translation initiation from the same mRNA under different stress conditions that induce DNA damage, ionizing radiation and endoplasmic reticulum (ER) stress, oncogene-induced senescence and cancer. [2][3][4][5][6][7] Thus, p53 mRNA has a dual IRES structure. 8 For their function, these IRESs rely on IRES trans-acting factors (ITAFs). Polypyrimidine-tract-binding protein (PTB) was shown to have differential affinity for the two IRESs of p53 and regulated p53 IRES functions by translocating from nucleus to cytoplasm on doxorubicin-induced DNA damage. 3 This PTB-med...

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Section: Resultsmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Reversible induction of translational isoforms of p53 in glucose deprivation

et al. 2015

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“…The suppression of PERK activity, 14-3-3s expression or deletion of the ER stress response IRES of p53/47 all result in an inhibition of UPR-induced G2/ M arrest. Together, this suggests that although p53/47 activates 14-3-3s, it also suppresses the induction of p21 CDKN1A/Cip1 and, thus, prevents the cells from arresting in G1/S while favouring a G2/M block (Bourougaa et al, 2010). In addition, expression of full-length p53 (p53FL) alone does not induce G2 arrest, but induces only GI arrest.…”

Section: Introductionmentioning

confidence: 99%

“…Further work showed that suppression of PERK activity, through overexpression of either a dominant-negative PERK or small interfering RNA, resulted in the suppression of p53/47 expression, indicating that PERK is the signal transducer between the ER and p53/47 expression ( Figure 2) (Bourougaa et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

p53 isoforms gain functions

Olivares‐Illana

Fåhræus

2010

Oncogene

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Many different cell stress pathways converge on p53 to induce a number of distinct cell biological responses such as G1 or G2 arrest, senescence or apoptosis. One of the outstanding questions with regard to p53 is how the cells can differentiate between different stresses so that p53 activation leads to the correct response. It has been known for some time that the p53 gene expresses isoforms that carry unique domains and properties, and more recent works have started to reveal some of their functions. The alternative mRNA translation product p53/47, which lacks the first 40 codons, including the first of p53's two trans-activation domains, is being linked to endoplasmic reticulum stress and the unfolded protein response to which it causes a specific G2 arrest. On the other hand, p53 itself induces G1 arrest and has no effect on the G2. The two isoforms D133p53, which lacks the first 133 amino acids, and p53b, which carries an alternative C-terminus, are derived from alternative promoter usage or splicing, respectively, and are together implied in controlling cellular senescence. Hence, through different mechanisms of gene expression control, alternative levels of p53 isoforms help the cell to differentiate between p53 activation and the response to diverse stresses. This holds promise to a better understanding of how upstream and downstream p53 pathways have evolved relative to specific p53 domains.

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Effect of p53 and its N‐terminally truncated isoform, Δ40p53, on breast cancer migration and invasion

et al. 2021

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Breast cancer is the most diagnosed malignancy in women, with over half a million women dying from this disease each year. In our previous studies, ∆40p53, an N‐terminally truncated p53 isoform, was found to be upregulated in breast cancers, and a high ∆40p53 : p53α ratio was linked with worse disease‐free survival. Although p53α inhibits cancer migration and invasion, little is known about the role of ∆40p53 in regulating these metastasis‐related processes and its role in contributing to worse prognosis. The aim of this study was to assess the role of ∆40p53 in breast cancer migration and invasion. A relationship between Δ40p53 and gene expression profiles was identified in oestrogen‐receptor‐positive breast cancer specimens. To further evaluate the role of Δ40p53 in oestrogen‐receptor‐positive breast cancer, MCF‐7 and ZR75‐1 cell lines were transduced to knockdown p53α or Δ40p53 and overexpress Δ40p53. Proliferation, migration and invasion were assessed in the transduced sublines, and gene expression was assessed through RNA‐sequencing and validated by reverse‐transcription quantitative PCR. Knockdown of both p53α and ∆40p53 resulted in increased proliferation, whereas overexpression of ∆40p53 reduced proliferation rates. p53α knockdown was also associated with increased cell mobility. ∆40p53 overexpression reduced both migratory and invasive properties of the transduced cells. Phenotypic findings are supported by gene expression data, including differential expression of LRG1, HYOU1, UBE2QL1, SERPINA5 and PCDH7. Taken together, these results suggest that, at the basal level, ∆40p53 works similarly to p53α in suppressing cellular mobility and proliferation, although the role of Δ40p53 may be cell context‐specific.

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Endoplasmic Reticulum Stress Induces G2 Cell-Cycle Arrest via mRNA Translation of the p53 Isoform p53/47

Cited by 146 publications

References 43 publications

Reversible induction of translational isoforms of p53 in glucose deprivation

Reversible induction of translational isoforms of p53 in glucose deprivation

p53 isoforms gain functions

Effect of p53 and its N‐terminally truncated isoform, Δ40p53, on breast cancer migration and invasion

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