Mitogen-Activated Protein Kinase-Interacting Kinase Regulates mTOR/AKT Signaling and Controls the Serine/Arginine-Rich Protein Kinase-Responsive Type 1 Internal Ribosome Entry Site-Mediated Translation and Viral Oncolysis

Brown, Michael C.; Dobrikov, Mikhail I.; Gromeier, Matthias

doi:10.1128/jvi.01884-14

Cited by 39 publications

(47 citation statements)

References 44 publications

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“…We recently identified a novel connection between MNK and mTOR signaling, that has profound implications for the homeostatic balance of mitogenic signaling in cancer cells and is liable to exert important influence on post-transcriptional gene regulatory systems, e.g. translation control [23,24]. We believe that our observations explain the remarkably specific and efficient translation, propagation and cytotoxicity of PVSRIPO in malignant cells [4].…”

Section: Pvsripo Targets Neoplasia-specific Conditions For Translatiomentioning

confidence: 88%

“…These affect an IRES region coordinating assembly and/or function of ribonucleoprotein complexes (RNPs) containing canonical translation factors (eukaryotic initiation factor (eIF) 4G, eIF4A, eIF4B; [18,19]) and, possibly, accessory IRES trans -acting factors (ITAFs; e.g. poly(rC) binding protein 2 (PCBP2); Ser-Arg (SR) rich protein 20 (SRp20); [18–22]) [23,24]. The IRES RNP recruits 40S ribosomal subunits (e.g.…”

Section: Pvsripo Targets Neoplasia-specific Conditions For Translatiomentioning

confidence: 99%

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Cytotoxic and immunogenic mechanisms of recombinant oncolytic poliovirus

Brown

Gromeier

2015

Current Opinion in Virology

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An oncolytic virus (OV) based on poliovirus (PV), the highly attenuated polio-/rhinovirus recombinant PVSRIPO, may deliver targeted inflammatory cancer cell killing; a principle that is showing promise in clinical trials for recurrent glioblastoma (GBM). The two decisive factors in PVSRIPO anti-tumor efficacy are selective cytotoxicity and its in situ immunogenic imprint. While our work is focused on what constitutes PVSRIPO cancer cytotoxicity, we are also studying how this engenders host immune responses that are vital to tumor regression. We hypothesize that PVSRIPO cytotoxicity and immunogenicity are inextricably linked in essential, complimentary roles that define the anti-neoplastic response. Herein we delineate mechanisms we unraveled to decipher the basis for PVSRIPO cytotoxicity and its immunotherapeutic potential.

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Section: Pvsripo Targets Neoplasia-specific Conditions For Translatiomentioning

confidence: 88%

Section: Pvsripo Targets Neoplasia-specific Conditions For Translatiomentioning

confidence: 99%

Cytotoxic and immunogenic mechanisms of recombinant oncolytic poliovirus

Brown

Gromeier

2015

Current Opinion in Virology

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“…A key question emerging from our studies is the mechanism underlying MNK-mediated control over SRPK, since SRPK is not a plausible MNK substrate. This question is addressed in a companion report, which revealed important information on an unexpected broad and deep involvement of MNK in mitogenic signal transduction networks impinging on posttranscriptional gene regulation (39). Given their apparently critical role as host pathogenesis factors, elucidating the precise mechanism for the SR protein/SRp20 involvement in IRES-mediated translation is required; however, this is beyond the scope of this study.…”

Section: Discussionmentioning

confidence: 99%

“…Subsequent analyses (see Fig. 9 and our companion paper [39]) implicated a signal transduction network with preeminent roles in posttranscriptional gene regulation and no plausible involvement in PV entry processes. Also, MNK could influence HRV2 IRES competency specifically, e.g., through sequence-specific RNAbinding trans-acting factors, or generally, by broadly promoting generic conditions for cap-independent initiation.…”

Section: Resultsmentioning

confidence: 99%

Induction of Viral, 7-Methyl-Guanosine Cap-Independent Translation and Oncolysis by Mitogen-Activated Protein Kinase-Interacting Kinase-Mediated Effects on the Serine/Arginine-Rich Protein Kinase

Brown

Bryant

Dobrikova

et al. 2014

J Virol

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Protein synthesis, the most energy-consuming process in cells, responds to changing physiologic priorities, e.g., upon mitogenor stress-induced adaptations signaled through the mitogen-activated protein kinases (MAPKs). The prevailing status of protein synthesis machinery is a viral pathogenesis factor, particularly for plus-strand RNA viruses, where immediate translation of incoming viral RNAs shapes host-virus interactions. In this study, we unraveled signaling pathways centered on the ERK1/2 and p38␣ MAPK-interacting kinases MNK1/2 and their role in controlling 7-methyl-guanosine (m 7 G) "cap"-independent translation at enterovirus type 1 internal ribosomal entry sites (IRESs). Activation of Raf-MEK-ERK1/2 signals induced viral IRES-mediated translation in a manner dependent on MNK1/2. This effect was not due to MNK's known functions as eukaryotic initiation factor (eIF) 4G binding partner or eIF4E(S209) kinase. Rather, MNK catalytic activity enabled viral IRES-mediated translation/host cell cytotoxicity through negative regulation of the Ser/Arg (SR)-rich protein kinase (SRPK). Our investigations suggest that SRPK activity is a major determinant of type 1 IRES competency, host cell cytotoxicity, and viral proliferation in infected cells.

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“…Interpreting these studies with respect to an effect on translation per se is complicated by the ability of MNK to shuttle between the nucleus and cytoplasm and also to phosphorylate hnRNPA1 and PSF (91,92), which are RNA-binding proteins that could potentially affect IRES-driven translation. An additional, recently identified MNK target, the Ser/Arg-rich protein kinase, is involved in mRNA splicing, export, stability, and translational initiation of type I picornovirus IRESs (93,94); Ser/Arg-rich protein kinase phosphorylation could potentially account for MNK-related differences in IRES-driven translation between whole-cell and cell-free systems.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Mitogen-activated Protein Kinase (MAPK)-interacting Kinase (MNK) Preferentially Affects Translation of mRNAs Containing Both a 5′-Terminal Cap and Hairpin

Korneeva

Song

Gram

et al. 2016

Journal of Biological Chemistry

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The MAPK-interacting kinases 1 and 2 (MNK1 and MNK2) are activated by extracellular signal-regulated kinases 1 and 2 (ERK1/2) or p38 in response to cellular stress and extracellular stimuli that include growth factors, cytokines, and hormones. Modulation of MNK activity affects translation of mRNAs involved in the cell cycle, cancer progression, and cell survival. However, the mechanism by which MNK selectively affects translation of these mRNAs is not understood. MNK binds eukaryotic translation initiation factor 4G (eIF4G) and phosphorylates the cap-binding protein eIF4E. Using a cell-free translation system from rabbit reticulocytes programmed with mRNAs containing different 5-ends, we show that an MNK inhibitor, CGP57380, affects translation of only those mRNAs that contain both a cap and a hairpin in the 5-UTR. Similarly, a C-terminal fragment of human eIF4G-1, eIF4G(1357-1600), which prevents binding of MNK to intact eIF4G, reduces eIF4E phosphorylation and inhibits translation of only capped and hairpin-containing mRNAs. Analysis of proteins bound to m 7 GTP-Sepharose reveals that both CGP and eIF4G(1357-1600) decrease binding of eIF4E to eIF4G. These data suggest that MNK stimulates translation only of mRNAs containing both a cap and 5-terminal RNA duplex via eIF4E phosphorylation, thereby enhancing the coupled cap-binding and RNA-unwinding activities of eIF4F.The rate of translational initiation in eukaryotic cells depends on both cis-acting features of individual mRNAs, such as the cap, poly(A) tract, and untranslated regions (UTRs), and trans-acting components, such as initiation factors, protein kinases, and microRNAs (1-3). The recruitment of capped mRNAs to 48S initiation complexes involves several discrete steps that include cap recognition by eukaryotic translation initiation factor 4E (eIF4E), 3 mRNA binding by eIF4G, ATP-dependent unwinding of 5Ј-terminal secondary structure by the helicase eIF4A in concert with eIF4B and eIF4H, recognition of the 3Ј-terminal poly(A) tract by poly(A)-binding protein (PABP), and binding of eIF4G to the 40S ribosomal subunit through eIF3. Both the primary and secondary structure of the 5Ј-UTR are capable of modulating translational efficiency (4, 5). mRNAs containing short 5Ј-UTRs with little secondary structure or terminal oligopyrimidine tracts are more efficiently translated under normal conditions with a limited level of eIF4E. Translational efficiency is diminished in mRNAs containing long, GϩC-rich, and highly structured 5Ј-UTRs because of the necessity for energy-dependent unwinding prior to start codon recognition (6). Translation of these mRNAs requires high levels of eIF4F, the complex of eIF4E, eIF4A, and eIF4G (3, 7). The availability of eIF4E to enter the eIF4F complex is regulated by the PI3K/Akt/mTOR signaling cascade; eIF4E is sequestered by binding to the 4E-BPs, but activation of the mTOR kinase causes phosphorylation of the 4E-BPs and release of eIF4E (8, 9). The activity of eIF4E can be also regulated by phosphorylation via the mitogen-activat...

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Mitogen-Activated Protein Kinase-Interacting Kinase Regulates mTOR/AKT Signaling and Controls the Serine/Arginine-Rich Protein Kinase-Responsive Type 1 Internal Ribosome Entry Site-Mediated Translation and Viral Oncolysis

Cited by 39 publications

References 44 publications

Cytotoxic and immunogenic mechanisms of recombinant oncolytic poliovirus

Cytotoxic and immunogenic mechanisms of recombinant oncolytic poliovirus

Induction of Viral, 7-Methyl-Guanosine Cap-Independent Translation and Oncolysis by Mitogen-Activated Protein Kinase-Interacting Kinase-Mediated Effects on the Serine/Arginine-Rich Protein Kinase

Inhibition of Mitogen-activated Protein Kinase (MAPK)-interacting Kinase (MNK) Preferentially Affects Translation of mRNAs Containing Both a 5′-Terminal Cap and Hairpin

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