PERK and PKR: Old kinases learn new tricks

Raven, Jennifer F.; Koromilas, Antonis E.

doi:10.4161/cc.7.9.5811

Cited by 82 publications

(66 citation statements)

References 39 publications

(52 reference statements)

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“…Despite their diverse regulatory domains, the kinase domains of these enzymes are significantly conserved explaining their specificity toward eIF2α (2). In addition to their function in phosphorylating eIF2α, there has been strong evidence to suggest that mammalian eIF2α kinases can also mediate biological effects independent of eIF2α phosphorylation (5)(6)(7).…”

Section: Introductionmentioning

confidence: 99%

eIF2α Kinase PKR Modulates the Hypoxic Response by Stat3-Dependent Transcriptional Suppression of HIF-1α

et al. 2010

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Hypoxia within the tumor microenvironment promotes angiogenesis, metabolic reprogramming, and tumor progression. In addition to activating hypoxia-inducible factor-1α (HIF-1α), cells also respond to hypoxia by globally inhibiting protein synthesis via serine 51 phosphorylation of translation eukaryotic initiation factor 2α (eIF2α). In this study, we investigated potential roles for stress-activated eIF2α kinases in regulation of HIF-1α. Our investigations revealed that the double-stranded RNA-dependent protein kinase R (PKR) plays a significant role in suppressing HIF-1α expression, acting specifically at the level of transcription. HIF-1α transcriptional repression by PKR was sufficient to impair the hypoxia-induced accumulation of HIF-1α and transcriptional induction of HIF-1α-dependent target genes. Inhibition of HIF-1A transcription by PKR was independent of eIF2α phosphorylation but dependent on inhibition of the signal transducer and activator of transcription 3 (Stat3). Furthermore, HIF-1A repression required the T-cell protein tyrosine phosphatase, which acts downstream of PKR, to suppress Stat3. Our findings reveal a novel tumor suppressor function for PKR, which inhibits HIF-1α expression through Stat3 but is independent of eIF2α phosphorylation. Cancer Res; 70(20); 7820-9. ©2010 AACR.

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Section: Introductionmentioning

confidence: 99%

eIF2α Kinase PKR Modulates the Hypoxic Response by Stat3-Dependent Transcriptional Suppression of HIF-1α

et al. 2010

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“…5,6 Although eIF2a phosphorylation has a major role in mediating the biological effects of the eIF2a kinases, their ability to function independently of eIF2a phosphorylation has been reported. 7,8 Previous findings provided evidence that eIF2a phosphorylation is induced by genotoxic stress. That is, GCN2, PERK and PKR have been implicated in the DNA damage response (DDR) by various stimuli.…”

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confidence: 99%

“…5,6 Although eIF2a phosphorylation has a major role in mediating the biological effects of the eIF2a kinases, their ability to function independently of eIF2a phosphorylation has been reported. 7,8 Received 21.12.09; revised 19.5.10; accepted 19.5.10; Edited by RA Knight; published online 18.6.10 These authors contributed equally to this work. …”

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confidence: 99%

Doxorubicin bypasses the cytoprotective effects of eIF2α phosphorylation and promotes PKR-mediated cell death

et al. 2010

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The eukaryotic cell responds to various forms of environmental stress by adjusting the rates of mRNA translation thus facilitating adaptation to the assaulting stress. One of the major pathways that control protein synthesis involves the phosphorylation of the a-subunit of eukaryotic initiation factor eIF2 at serine 51. Different forms of DNA damage were shown to induce eIF2a phosphorylation by using PERK, GCN2 or PKR. However, the specificity of the eIF2a kinases and the biological role of eIF2a phosphorylation pathway in the DNA damage response (DDR) induced by chemotherapeutics are not known. Herein, we show that PKR is the eIF2a kinase that responds to DDR induced by doxorubicin. We show that activation of PKR integrates two signaling pathways with opposing biological outcomes. More specifically, induction of eIF2a phosphorylation has a cytoprotective role, whereas activation of c-jun N-terminal kinase (JNK) by PKR promotes cell death in response to doxorubicin. We further show that the proapoptotic effects of JNK activation prevail over the cytoprotection mediated by eIF2a phosphorylation. These findings reveal that PKR can be an important inducer of cell death in response to chemotherapies through its ability to act independently of eIF2a phosphorylation. The eukaryotic cell has established intricate mechanisms to cope with environmental stress. It does so by changing protein expression in a manner that promotes adaptation to the assaulting stress. Protein expression within the cell is regulated at the transcriptional, translational and posttranslational levels. Translational control is often used under conditions of cellular stress because it allows immediate and selective changes in protein levels. 1 Translation itself is divided into three distinct phases: initiation, elongation and termination. By far the most explored step is that of initiation, which has been shown to be regulated by different extracellular stimuli. 1 One of the major pathways that control translation initiation is that of the phosphorylation of the a-subunit of translation initiation factor eIF2. 2 Phosphorylation of eIF2a at serine 51 (S51) leads to the inhibition of global protein synthesis providing the cell with the opportunity to elicit adaptive responses not only by saving energy but also by preventing the accumulation of unwanted proteins that could interfere with cellular functions. 1 There are four eIF2a kinases that share a homologous kinase domain (KD) but possess different regulatory domains that enable them to become activated by distinct stimuli. 2 The eIF2a kinases are the heme-regulated inhibitor, which is found mainly in erythroid cells and is activated by heme deficiency; the endoplasmic reticulum (ER)-resident kinase (PERK), which is activated by ER stress and inhibits protein synthesis as part of the unfolded protein response; the general aminoacid nonderepressing kinase 2 (GCN2), which responds to amino-acid deprivation and becomes activated by uncharged tRNA and the RNA-dependent protein kinase PKR, an interfer...

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“…67 It has been shown that ER stress and the UPR can be a potent inducer of autophagic cell death pathways. 68,69 In multiple prior studies activation of p38 MAPK and/or the JNK pathway was demonstrated to be causal in MDA-7/IL-24 lethality. In fibroblasts and GBM cells MDA-7/IL-24-induced JNK1-3 activation was PERK-dependent, and JNK signaling initiated mitochondrial dysfunction.…”

Section: Diverse Molecular and Signal Transduction Pathways Involved mentioning

confidence: 99%

Historical perspective and recent insights into our understanding of the molecular and biochemical basis of the antitumor properties of mda-7/IL-24

Emdad

Lebedeva

et al. 2009

Cancer Biology & Therapy

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A subtraction hybridization approach combined with a differentiation therapy model of human melanoma identified melanoma differentiation associated gene-7 (mda-7) as a gene upregulated during induction of terminal differentiation. Based on conserved structure, chromosomal location and cytokine-like properties, mda-7, has now been classified as a member of the expanding interleukin (IL)-10 gene family and designated as mda-7/IL-24. Extensive in vitro and in vivo human tumor xenograft studies confirm that mda-7/IL-24 induces apoptosis specifically in tumor cells without harming normal cells. Unique properties of mda-7/IL-24 action also include potent "bystander antitumor" activity, an ability to exert anti-angiogenic effects, immune modulating ability and a capacity to enhance the sensitivity of tumor cells to radiotherapy, chemotherapy and monoclonal antibody therapy. Very recent studies from our groups further reveal autocrine regulation and chemoprevention facilitating properties of mda-7/IL-24. Based on these remarkable antitumor attributes, mda-7/IL-24 was evaluated by intratumoral injection with a replication incompetent adenovirus expressing this gene (Ad.mda-7; INGN 241) in a phase I clinical trial in patients with metastatic melanomas and other advanced solid cancers. mda-7/IL-24 was well tolerated with significant clinical activity. This review highlights our current understanding of the molecular and biochemical basis of mda-7/IL-24 antitumor properties and highlights its potential as a viable gene-based therapy for a wide spectrum of primary and advanced cancers.

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PERK and PKR: Old kinases learn new tricks

Cited by 82 publications

References 39 publications

eIF2α Kinase PKR Modulates the Hypoxic Response by Stat3-Dependent Transcriptional Suppression of HIF-1α

eIF2α Kinase PKR Modulates the Hypoxic Response by Stat3-Dependent Transcriptional Suppression of HIF-1α

Doxorubicin bypasses the cytoprotective effects of eIF2α phosphorylation and promotes PKR-mediated cell death

Historical perspective and recent insights into our understanding of the molecular and biochemical basis of the antitumor properties of mda-7/IL-24

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