<scp>eIF</scp>2α kinases <scp>PERK</scp> and <scp>GCN</scp>2 act on <scp>FOXO</scp> to potentiate <scp>FOXO</scp> activity

You, Shiqiu; Li, Huifang; Hu, Zhubing; Zhang, Wei

doi:10.1111/gtc.12625

Cited by 12 publications

(11 citation statements)

References 36 publications

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“…From the nucleus, NRF2 coordinates the expression of the antioxidant response by binding the antioxidant response elements (AREs) present in the regulatory regions of several genes [79]. Additional studies have revealed that FOXO transcription factors [80,81] and diacylglycerol [82,83] can also be phosphorylated by PERK in order to reduce ER stress. Other PERK-related kinases exist that can supervise different stress conditions.…”

Section: Cellular Responses To the Unfolded Proteinsmentioning

confidence: 99%

Proteotoxic Stress and Cell Death in Cancer Cells

Brancolini

Iuliano

2020

Cancers

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To maintain proteostasis, cells must integrate information and activities that supervise protein synthesis, protein folding, conformational stability, and also protein degradation. Extrinsic and intrinsic conditions can both impact normal proteostasis, causing the appearance of proteotoxic stress. Initially, proteotoxic stress elicits adaptive responses aimed at restoring proteostasis, allowing cells to survive the stress condition. However, if the proteostasis restoration fails, a permanent and sustained proteotoxic stress can be deleterious, and cell death ensues. Many cancer cells convive with high levels of proteotoxic stress, and this condition could be exploited from a therapeutic perspective. Understanding the cell death pathways engaged by proteotoxic stress is instrumental to better hijack the proliferative fate of cancer cells.

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Section: Cellular Responses To the Unfolded Proteinsmentioning

confidence: 99%

Proteotoxic Stress and Cell Death in Cancer Cells

Brancolini

Iuliano

2020

Cancers

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“…It is a common phenomenon that PERK and GCN2 kinases simultaneously regulate the same substrate (Hamanaka et al, 2005;Krishnamoorthy et al, 2008;You et al, 2018;Jin et al, 2019). We used PERK or GCN2 inhibitor to treat DEFs and found that both inhibitors can attenuate eIF2α phosphorylation, related to the redundancy or even compensation of the two kinases' functions (Donnelly et al, 2013;You et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Duck Hepatitis A Virus Type 1 Induces eIF2α Phosphorylation-Dependent Cellular Translation Shutoff via PERK/GCN2

et al. 2021

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Duck hepatitis A virus type 1 (DHAV-1) is one of the most deadly pathogens that endanger the duck industry. Most viruses usually turn off host translation after infection to facilitate viral replication and translation. For the first time report to our knowledge, DHAV-1 can induce eIF2α phosphorylation and inhibit cellular translation in duck embryo fibroblasts (DEFs). Moreover, the activity of DHAV-1 in the cells caused obvious eIF2α phosphorylation, which has nothing to do with the viral protein. Subsequently, we screened two kinases (PERK and GCN2) that affect eIF2α phosphorylation through inhibitors and shRNA. Notably, the role of GCN2 in other picornaviruses has not been reported. In addition, when the phosphorylation of eIF2α induced by DHAV-1 is inhibited, the translation efficiency of DEFs restores to a normal level, indicating that DHAV-1 induced cellular translation shutoff is dependent on eIF2α phosphorylation.

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“…However, despite pharmaceutical inhibitors of PERK having demonstrated good anticancer activities in combination therapies, their effectiveness as a single agent is limited, suggesting the existence of possible compensatory cellular responses ( Axten et al, 2012 , 2013 ; Bi et al, 2005 ; Salaroglio et al, 2017 ). Previous studies in Drosophila have shown that GCN2 (eIF2AK4) and PERK (eIF2AK3) can cooperate to modulate FOXO activity in response to ER stress ( You et al, 2018 ; Zhang et al, 2013 ), suggesting the PERK-related GCN2 can potentially compensate for the inactivation of PERK function in cancer cells. However, in contrast to our finding in human breast cancer cells ( Alasiri et al, 2019 ), these studies in flies suggest that both GCN2 and PERK potentiate rather than repress FOXO activity in response to ER stress ( You et al, 2018 ; Zhang et al, 2013 ).…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies in Drosophila have shown that GCN2 (eIF2AK4) and PERK (eIF2AK3) can cooperate to modulate FOXO activity in response to ER stress ( You et al, 2018 ; Zhang et al, 2013 ), suggesting the PERK-related GCN2 can potentially compensate for the inactivation of PERK function in cancer cells. However, in contrast to our finding in human breast cancer cells ( Alasiri et al, 2019 ), these studies in flies suggest that both GCN2 and PERK potentiate rather than repress FOXO activity in response to ER stress ( You et al, 2018 ; Zhang et al, 2013 ). Nevertheless, the time-course drug treatment experiments on the parental MCF-7 and drug resistant MCF-7Epi R and MCF-7Tax R breast cancer cells lent support to the idea that GCN2 can potentially cooperate with PERK to repress FOXO3 activity via JNK and AKT to modulate drug response and compensate for PERK inactivation.…”

Section: Discussionmentioning

confidence: 99%

“…Although different eIF2AKs recognise distinct cellular metabolic stress signals, a recent study has demonstrated that PERK (eIFA2K3) and (eIF2AK4) function cooperatively to promote cell survival during paclitaxel treatment in vitro and in vivo ( Chen et al, 2019 ). Previous studies in Drosophila have also shown that both GCN2 and PERK can potentiate FOXO activity in response to ER stress ( You et al, 2018 ,Zhang et al). In agreement, a recent study also demonstrated that PERK and GCN2 activate MYC, a proto-oncogenic bHLH transcription factor which engages in tumour growth and proliferation, and its activation is responsible for the tumorigenesis of many human cancers ( Tameire et al, 2019 ).…”

Section: Introductionmentioning

confidence: 90%

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Reciprocal regulation between GCN2 (eIF2AK4) and PERK (eIF2AK3) through the JNK-FOXO3 axis to modulate cancer drug resistance and clonal survival

Alasiri

Jiramongkol

Trakansuebkul

et al. 2020

Molecular and Cellular Endocrinology

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Pharmaceutical inhibitors of the endoplasmic reticulum (ER)-stress modulator PERK (eIF2AK3) have demonstrated anticancer activities in combination therapies, but their effectiveness as a single agent is limited, suggesting the existence of possible compensatory cellular responses. To explore the potential mechanisms involved, we performed time-course drug treatment experiments on the parental MCF-7 and drug resistant MCF-7Epi R and MCF-7Tax R breast cancer cells and identified GCN2 (eIF2AK4) as a molecule that can potentially cooperate with PERK to regulate FOXO3 via JNK and AKT to modulate drug response. Consistently, GCN2 knockdown severely impaired the clonal survival of parental and resistant MCF-7 cells and sensitised them to epirubicin and paclitaxel treatment. Western blot, RT-qPCR and ChIP analyses also confirmed that GCN2 inactivation causes an induction of JNK and thereby FOXO3 activity, culminating in an increase in PERK activity and expression at the transcription level. Conversely, PERK-inactivation using GSK2606414-induces an induction in GCN2 expression and activity also associated with JNK. In agreement, we also showed that the perk −/− MEFs, expressing elevated levels of P-JNK, JNK, GCN2 and reduced levels of P-AKT and P-FOXO3, have lower clonogenicity and are more sensitive to epirubicin compared to wild-type MEFs. Similarly, gcn2 −/− MEFs expressing augmented levels of P-JNK, JNK, P-PERK, PERK and lower levels of P-AKT and P-FOXO3 also had lower clonogenicity and were more sensitive to epirubicin and PERK-inhibition. In addition, JNK1/2 deletion in MEFs resulted in reduced levels of GCN2, FOXO3, PERK, P-PERK expression as well as FOXO3 activity and enhanced clonal survival and resistance to PERK-inhibition. Together these results demonstrate that GCN2 cooperates with PERK through the JNK-FOXO3 axis in a reciprocal negative feedback loop to mediate cancer chemotherapeutic drug response and clonal survival, advocating the potential of targeting GCN2 as a therapeutic strategy for treating cancer and for overcoming drug resistance.

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eIF2α kinases PERK and GCN2 act on FOXO to potentiate FOXO activity

Cited by 12 publications

References 36 publications

Proteotoxic Stress and Cell Death in Cancer Cells

Proteotoxic Stress and Cell Death in Cancer Cells

Duck Hepatitis A Virus Type 1 Induces eIF2α Phosphorylation-Dependent Cellular Translation Shutoff via PERK/GCN2

Reciprocal regulation between GCN2 (eIF2AK4) and PERK (eIF2AK3) through the JNK-FOXO3 axis to modulate cancer drug resistance and clonal survival

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