The PERK/eIF2α/ATF4 module of the UPR in hypoxia resistance and tumor growth

Fels, Diane; Koumenis, Constantinos

doi:10.4161/cbt.5.7.2967

Cited by 320 publications

(240 citation statements)

References 60 publications

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“…The PERK arm of the UPR also plays important role in tumor proliferation and survival. Inactivation of the PERK pathway by either generating mutations in the kinase domain of PERK or introducing a phosphorylation-resistant form of eIF2a impairs cell survival under extreme hypoxia [83]. Furthermore, PERK limits oxidative DNA damage through Nrf2 activation which further promotes cancer cell proliferation and survival [84].…”

Section: Er Stress and Cancermentioning

confidence: 99%

Role of Endoplasmic Reticulum Stress and Unfolded Protein Responses in Health and Diseases

2015

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Endoplasmic reticulum (ER) is the site of protein synthesis, protein folding, maintainance of calcium homeostasis, synthesis of lipids and sterols. Genetic or environmental insults can alter its function generating ER stress. ER senses stress mainly by three stress sensor pathways, namely protein kinase R-like endoplasmic reticulum kinase-eukaryotic translation-initiation factor 2a, inositol-requiring enzyme 1a-X-box-binding protein 1 and activating transcription factor 6-CREBH, which induce unfolded protein responses (UPR) after the recognition of stress. Recent studies have demonstrated that ER stress and UPR signaling are involved in cancer, metabolic disorders, inflammatory diseases, osteoporosis and neurodegenerative diseases. However, the precise knowledge regarding involvement of ER stress in different disease processes is still debatable. Here we discuss the possible role of ER stress in various disorders on the basis of existing literature. An attempt has also been made to highlight the present knowledge of this field which may help to elucidate and conjure basic mechanisms and novel insights into disease processes which could assist in devising better future diagnostic and therapeutic strategies.

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Section: Er Stress and Cancermentioning

confidence: 99%

Role of Endoplasmic Reticulum Stress and Unfolded Protein Responses in Health and Diseases

2015

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“…Several cellular conditions, such as high demand for protein synthesis and secretion (3,4), viral infection (5), deprivation of nutrients/oxygen (6,7), and missense mutations affecting both client protein folding (8 -11) and ER folding machinery function (2) enhance protein misfolding and cause accumulation of unfolded or misfolded proteins, leading to ER stress. Mammalian cells use several adaptive mechanisms, collectively known as the unfolded protein response (UPR), to cope with acute ER stress (12).…”

Section: The Endoplasmic Reticulum (Er)mentioning

confidence: 99%

Deficiency of Suppressor Enhancer Lin12 1 Like (SEL1L) in Mice Leads to Systemic Endoplasmic Reticulum Stress and Embryonic Lethality

Francisco

Singh

et al. 2010

Journal of Biological Chemistry

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Stress in the endoplasmic reticulum (ER) plays an important causal role in the pathogenesis of several chronic diseases such as Alzheimer, Parkinson, and diabetes mellitus. Insight into the genetic determinants responsible for ER homeostasis will greatly facilitate the development of therapeutic strategies for the treatment of these debilitating diseases. Suppressor enhancer Lin12 1 like (SEL1L) is an ER membrane protein and was thought to be involved in the quality control of secreted proteins. Here we show that the mice homozygous mutant for SEL1L were embryonic lethal. Electron microscopy studies revealed a severely dilated ER in the fetal liver of mutant embryos, indicative of alteration in ER homeostasis. Consistent with this, several ER stress responsive genes were significantly up-regulated in the mutant embryos. Mouse embryonic fibroblast cells deficient in SEL1L exhibited activated unfolded protein response at the basal state, impaired ER-associated protein degradation, and reduced protein secretion. Furthermore, markedly increased apoptosis was observed in the forebrain and dorsal root ganglions of mutant embryos. Taken together, our results demonstrate an essential role for SEL1L in protein quality control during mouse embryonic development.

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“…(20,23) Recently, the UPR has received considerable attention as a potential target for anticancer therapy. (6,7,10,24) We have shown that versipelostatin (VST), a small molecule compound, can disrupt the UPR during glucose deprivation.(25) Indeed, under that stressor, VST inhibits GRP78 and GRP94 induction and represses the production of the UPR transcription activators ATF4 and X-box protein (XBP)1. VST shows highly selective cytotoxicity to glucose-deprived tumor cells and exerts in vivo antitumor activity at well-tolerated doses.…”

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confidence: 99%

Preventing the unfolded protein response via aberrant activation of 4E‐binding protein 1 by versipelostatin

et al. 2009

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We recently isolated a macrocyclic compound, versipelostatin (VST), that exerts in vivo antitumor activity. VST shows unique, selective cytotoxicity to glucose-deprived tumor cells by preventing the unfolded protein response (UPR). Here we show that eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), a negative regulator of eukaryotic initiation factor 4E-mediated protein translation, plays a role in the UPR-inhibitory action of VST. Indeed, 4E-BP1 is aberrantly activated by VST. This activation occurs specifically during glucose deprivation and results in profound translation repression and prevents induction of the typical UPR markers glucose-regulated protein (GRP) 78 and activating transcription factor (ATF) 4. Our overexpression and knockdown experiments showed that 4E-BP1 can regulate GRP78 and ATF4 expression. These mechanisms appear to be specific for VST. By contrast, rapamycin, which activates 4E-BP1 regardless of cellular glucose availability, has only marginal effects on the expression of GRP78 and ATF4. Our present findings demonstrate that aberrant 4E-BP1 activation can contribute to UPR preventing by VST, possibly through a mechanism that does not operate in rapamycin-treated cells. (Cancer Sci 2009; 100: 327-333) S olid tumors have regions of low glucose and low oxygen (hypoxia) that arise from immature and irregular distribution of microvasculature.(1,2) In this stressful microenvironment, tumor cells are thought to survive by activating adaptive response pathways.(3) An important response for tumor development is the unfolded protein response (UPR), which can be activated in tumor cells during glucose deprivation as well as hypoxia.(4,5) The UPR has also been associated with lowered chemosensitivity in breast cancer and gliomas. (6,7) The UPR is a regulatory network that allows the cells to cope with stress that leads to the accumulation of misfolded or unfolded proteins in the endoplasmic reticulum (ER).(8) The main signaling pathways are sensed and initiated by the ERlocalized transmembrane proteins Double-standard RNA-dependent Protein Kinase (PKR)-like ER kinase (PERK), inositol-requiring 1 (IRE1), and activating transcription factor (ATF) 6.(8) These signaling pathways reduce global translation and produce several different active transcription factors to induce divergent UPR target genes, such as the ER-resident molecular chaperones glucose-regulated protein (GRP) 78 and GRP94. (5,8,9) Thus, during the UPR, both translational and transcriptional control mechanisms operate to relieve ER stress to allow for cell survival. (9)(10)(11)(12) In the case of intolerable levels of ER stress, however, the sensor proteins can contribute to apoptosis. (9)(10)(11)(12)(13) In the UPR translational control, PERK plays a major role by phosphorylating eukaryotic initiation factor (eIF) 2α at Ser51. (12,14) Phosphorylation of eIF2α reduces global translation and, paradoxically, directs preferential translation of ATF4, a UPR transcription activator.(15) The signaling pathway is further regulated by...

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The PERK/eIF2α/ATF4 module of the UPR in hypoxia resistance and tumor growth

Cited by 320 publications

References 60 publications

Role of Endoplasmic Reticulum Stress and Unfolded Protein Responses in Health and Diseases

Role of Endoplasmic Reticulum Stress and Unfolded Protein Responses in Health and Diseases

Deficiency of Suppressor Enhancer Lin12 1 Like (SEL1L) in Mice Leads to Systemic Endoplasmic Reticulum Stress and Embryonic Lethality

Preventing the unfolded protein response via aberrant activation of 4E‐binding protein 1 by versipelostatin

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