p53-mediated suppression of BiP triggers BIK-induced apoptosis during prolonged endoplasmic reticulum stress

López, Ignacio; Tournillon, Anne-Sophie; Martins, Rodrigo Prado; Karakostis, Konstantinos; Malbert-Colas, Laurence; Nylander, Karin; Fåhræus, Robin

doi:10.1038/cdd.2017.96

Cited by 49 publications

(44 citation statements)

References 58 publications

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“…Consistent with these above reports, we identify that lncRNA MEG3 could directly bind to and regulate p53 expression in NMVMs by RIP and Western blot assays, but which were not entirely the same as Wu.et al research . Previous studies have found that p53 could also regulate the levels of GRP78, CHOP and Bax, which exerted key roles in the process of ERS, leading to apoptosis . However, the regulatory mechanism between p53 and ERS remains unclear.…”

Section: Discussionsupporting

confidence: 90%

“…28 Previous studies have found that p53 could also regulate the levels of GRP78, CHOP and Bax, which exerted key roles in the process of ERS, leading to apoptosis. [34][35][36] However, the regulatory mechanism between p53 and ERS remains unclear. Studies indicate that NF-κB signalling was reported to be a vital in regulating ERS-and p53-related myocardial apoptosis.…”

Section: Discussionmentioning

confidence: 99%

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Long non‐coding RNA MEG3 knockdown attenuates endoplasmic reticulum stress‐mediated apoptosis by targeting p53 following myocardial infarction

Zhao

Chen

et al. 2019

J Cellular Molecular Medi

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Mounting evidence has indicated that long non‐coding RNA maternally expressed gene 3 (lncRNA MEG3) regulates cell apoptosis, and is involved in a variety of diseases. However, its exact role in myocardial infarction (MI) has not been fully elucidated. In the present study, we firstly observed that the expression levels of the lncRNA MEG3 in infarct hearts and hypoxic neonatal mice ventricular myocytes (NMVMs) were up‐regulated by quantitative real‐time PCR (qRT‐PCR). Then, we knocked down lncRNA MEG3 by lentiviral delivery in the myocardial border region following multipoint injection. Following 28 days of MI, the lncRNA MEG3 knockdown mice indicated better cardiac function, and less cardiac remodelling by ultrasonic cardiogram and histological analysis. In addition, we indicated that lncRNA MEG3 knockdown reduced myocyte apoptosis and reactive oxygen species production in MI mice model and hypoxic NMVMs. Furthermore, we revealed that knockdown of lncRNA MEG3 protected against endoplasmic reticulum stress (ERS)‐mediated myocardial apoptosis including the induction of PERK‐eIF2α and caspase 12 pathways. At last, we provided evidence that p53 was identified as a protein target of lncRNA MEG3 to regulate NF‐κB‐ and ERS‐associated apoptosis. Taken collectively, our findings demonstrated that lncRNA MEG3 knockdown exerted cardioprotection by reducing ERS‐mediated apoptosis through targeting p53 post‐MI.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Long non‐coding RNA MEG3 knockdown attenuates endoplasmic reticulum stress‐mediated apoptosis by targeting p53 following myocardial infarction

Zhao

Chen

et al. 2019

J Cellular Molecular Medi

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“…This supports the notion that a pro-apoptotic response is more likely if the cell fails to arrest in G2 and to restore the ER homeostasis, in a similar fashion as the p53fl-dependent apoptosis is triggered when cells fail to arrest in G1 following genotoxic stress [20,25]. Interestingly, induction of apoptosis by p53 during ER stress relies, at least in part, on the suppression of BiP synthesis (Table 1) [98]. In addition to its chaperoning activity, BiP binds several partners, including the inducers of the UPR axis, that together control cell growth and protect against stress-induced apoptosis [99][100][101][102][103][104][105][106].…”

Section: Induction Of Apoptosissupporting

confidence: 74%

“…Accordingly, BiP is upregulated in various cancers, including brain, prostate, head and neck and melanoma [41,[107][108][109][110]. Though the molecular mechanisms remain largely unknown, BiP's mRNA interaction with p53 resulted in inhibition of BiP protein synthesis and therefore less interaction between BiP and Bcl-2-interacting killer (BIK), a pro-apoptotic member of the Bcl-2 family [98,106]. Remarkably, the p53-dependent drop in BiP/BIK association only occurred during ER stress, implying that stress conditions are also key in controlling the BiP-BIK interaction and cell fate decisions [98].…”

Section: Induction Of Apoptosismentioning

confidence: 99%

Alternative Mechanisms of p53 Action During the Unfolded Protein Response

Fusee

Marı́n

Fåhræus

et al. 2020

Cancers

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The tumor suppressor protein p53 orchestrates cellular responses to a vast number of stresses, with DNA damage and oncogenic activation being some of the best described. The capacity of p53 to control cellular events such as cell cycle progression, DNA repair, and apoptosis, to mention some, has been mostly linked to its role as a transcription factor. However, how p53 integrates different signaling cascades to promote a particular pathway remains an open question. One way to broaden its capacity to respond to different stimuli is by the expression of isoforms that can modulate the activities of the full-length protein. One of these isoforms is p47 (p53/47, ∆40p53, p53∆N40), an alternative translation initiation variant whose expression is specifically induced by the PERK kinase during the Unfolded Protein Response (UPR) following Endoplasmic Reticulum stress. Despite the increasing knowledge on the p53 pathway, its activity when the translation machinery is globally suppressed during the UPR remains poorly understood. Here, we focus on the expression of p47 and we propose that the alternative initiation of p53 mRNA translation offers a unique condition-dependent mechanism to differentiate p53 activity to control cell homeostasis during the UPR. We also discuss how the manipulation of these processes may influence cancer cell physiology in light of therapeutic approaches.Cancers 2020, 12, 401 2 of 17 carcinomas, and leukemia, particularly in children and young adults [6]. Patients with this syndrome generally express both the mutant and wild-type (p53wt) forms of p53 in all tissues. During cancer progression, the wild-type activity of the protein is often lost, either due to the occurrence of dominant-negative (DNE) inhibitor mutations, to a gain of function (GOF) mutation that favors cancer progression, or to a direct loss of p53wt allele, a phenomenon known as loss of heterozygosity (LOH) [1,6]. The important handicap imposed by expressing half of the normal amount of fully active p53 in Li-Fraumeni patients [1,7] highlights the sensitivity of the pathway to small changes in p53 levels.In tumor cells containing wild-type TP53 gene, p53 activity might be compromised through different mechanisms. A well-known example constitutes the inhibitory interaction of p53 with proteins from cancer-associated virus, such as the T antigen from SV40 [8,9], adenovirus E1b protein [10] and the E6 protein from human papilloma virus (HPV) types 16 and 18 [11,12]. Overexpression of cellular regulators such as Mouse double minute 2 homolog MDM2 [13] and its homolog MDMX (MDM4) [14] can also suppress p53 activity and therefore have oncogenic potential. Under normal conditions, MDM2 and MDMX bind the conserved BOX-I motif in the N-terminus of p53 and mask its transactivation (TA) domain [13][14][15][16]. Moreover, MDM2, but not MDMX, possesses an E3-ubiquitin ligase activity that relies on its C-terminal RING domain, and targets p53 for 26S-dependent proteasomal degradation [17].p53 activation during the DNA damage response (DDR) has...

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“…Previous studies have reported the association between P53 and UPR in malignancies. However, the outcomes appear to be tissue‐specific, since it was shown that the endoplasmic reticulum stress stimulates P53 expression through nuclear factor‐κB (NF‐κB) activation, while others have demonstrated the opposite effects in different experimental systems . Several studies have shown the correlation of endoplasmic reticulum stress and UPR to endothelial dysfunction in both animal and cellular models .…”

Section: Discussionmentioning

confidence: 99%

Unfolded protein response regulates P53 expression in the pulmonary endothelium

Akhter

Uddin

Barabutis

2019

J Biochem & Molecular Tox

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Lung endothelial barrier dysfunction leads to severe pathologies, including the lethal Acute Respiratory Distress Syndrome. P53 has been associated with anti‐inflammatory activities. The current study employs a variety of unfolded protein response (UPR) activators and inhibitors to investigate the regulation of P53 by UPR in lung cells. The bovine cells that were exposed to the UPR inductors brefeldin A, dithiothreitol, and thapsigargin; demonstrated elevated expression levels of P53 compared to the vehicle‐treated cells. On the contrary, the UPR inhibitors N‐acetyl cysteine, kifunensine, and ATP‐competitive IRE1α kinase‐inhibiting RNase attenuator; produced the opposite effects. The outcomes of the present study reveal a positive regulation between UPR and P53. Since it has been shown that a mild induction of the unfolded protein response opposes inflammation, we suggest that P53 is involved in those protective activities in the lung.

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p53-mediated suppression of BiP triggers BIK-induced apoptosis during prolonged endoplasmic reticulum stress

Cited by 49 publications

References 58 publications

Long non‐coding RNA MEG3 knockdown attenuates endoplasmic reticulum stress‐mediated apoptosis by targeting p53 following myocardial infarction

Long non‐coding RNA MEG3 knockdown attenuates endoplasmic reticulum stress‐mediated apoptosis by targeting p53 following myocardial infarction

Alternative Mechanisms of p53 Action During the Unfolded Protein Response

Unfolded protein response regulates P53 expression in the pulmonary endothelium

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