M7G-cap independent translation. This is due to broadly de-regulated mitogenic

M7G-cap independent translation. This is due to broadly de-regulated mitogenic signal transduction cascades that converge on translation machinery. For example, oncogenic H-Ras transduction of neuronlike HEK293 cells, which are resistant to PVSRIPO translation and cytotoxicity, fully restores HRV2 IRES competence and PVSRIPO translation/propagation. This effect is Author Manuscript Author Manuscript Author Manuscript Author Manuscript Curr Opin Virol. Author manuscript; available in PMC 2016 August 01. Brown and Gromeier Page 4 in large part due to the activation of the downstream ERK1/2 substrate, MAPK-interacting kinase . MNK is mainly known for phosphorylation of its signature substrate, the m7G-cap-binding protein eIF4E, but the functional consequences of this event for translation control remains obscure. 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 posttranscriptional gene regulatory systems, e.g. translation control. We believe that our observations explain the remarkably specific and efficient translation, propagation and cytotoxicity of PVSRIPO in malignant cells. We found that a major effect of ERK1/2MNK signaling is to temper runaway AKT AZ-6102 activity via stimulation of mTORC1/concomitant repression of mTORC2; ). This balancing between Ras-MEK-ERK1/2 and PI3K-AKT signaling, centered on the functions of MNK, relieves constitutive AKT-mediated activation of the Ser-Arg rich protein kinase to enhance PVSRIPO IRES-mediated translation and cytotoxicity. Indeed, in vivo studies using a GBM xenograft model revealed that upstream AKT inhibition enhances tumor regression when combined with PVSRIPO. While the mechanism by which SRPK activity restricts viral translation is currently under investigation, it is likely that nucleo-cytoplasmic shuttling SR proteins, principal substrates of SRPK, play a role. One SR protein in particular, SRp20, is a confirmed ITAF. We hypothesize that active SRPK-mediated phosphorylation of SRp20 may favor cytoplasmic accumulation and translation involvement of shuttling SR proteins, a scenario that was documented for the shuttling SR protein ASF/SF2. In cancerous cells, SRPK activity/SRp20 phosphorylation occurs at an equilibrium that facilitates IRES mediated translation. Of course it is likely that other events converging on translation machinery in transformed cells, e.g. those affecting eIF4G and its many binding partners in the translation initiation scaffold, also play a role in enabling unfettered PVSRIPO translation competence. Author Manuscript Author Manuscript Author Manuscript Author Manuscript Future perspectives To fully grasp the immunotherapeutic potential of PVSRIPO oncolysis, we have developed robust syngeneic murine 2883-98-9 chemical information models of GBM and other cancer types. These models will enable us discern how immunological events shape PVSRIPO cancer immunotherapy and to build a platform to test how PVSRIPO therapy may be broadened, enhanced or optimized. While another oncolytic PV construct was shown to produce efficacious antitumor CD8 T cell responses in a syngeneic murine cancer model, resolving issues such as: does PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/1985460 PVSRIPO oncolytic efficacy entirely rely on such responses what is the mechanism linking viral cytotoxicity and innate anti-viral immunity to the adaptive antitumor immune response are there tumor-specific or patient-speci.M7G-cap independent translation. This is due to broadly de-regulated mitogenic signal transduction cascades that converge on translation machinery. For example, oncogenic H-Ras transduction of neuronlike HEK293 cells, which are resistant to PVSRIPO translation and cytotoxicity, fully restores HRV2 IRES competence and PVSRIPO translation/propagation. This effect is Author Manuscript Author Manuscript Author Manuscript Author Manuscript Curr Opin Virol. Author manuscript; available in PMC 2016 August 01. Brown and Gromeier Page 4 in large part due to the activation of the downstream ERK1/2 substrate, MAPK-interacting kinase . MNK is mainly known for phosphorylation of its signature substrate, the m7G-cap-binding protein eIF4E, but the functional consequences of this event for translation control remains obscure. 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 posttranscriptional gene regulatory systems, e.g. translation control. We believe that our observations explain the remarkably specific and efficient translation, propagation and cytotoxicity of PVSRIPO in malignant cells. We found that a major effect of ERK1/2MNK signaling is to temper runaway AKT activity via stimulation of mTORC1/concomitant repression of mTORC2; ). This balancing between Ras-MEK-ERK1/2 and PI3K-AKT signaling, centered on the functions of MNK, relieves constitutive AKT-mediated activation of the Ser-Arg rich protein kinase to enhance PVSRIPO IRES-mediated translation and cytotoxicity. Indeed, in vivo studies using a GBM xenograft model revealed that upstream AKT inhibition enhances tumor regression when combined with PVSRIPO. While the mechanism by which SRPK activity restricts viral translation is currently under investigation, it is likely that nucleo-cytoplasmic shuttling SR proteins, principal substrates of SRPK, play a role. One SR protein in particular, SRp20, is a confirmed ITAF. We hypothesize that active SRPK-mediated phosphorylation of SRp20 may favor cytoplasmic accumulation and translation involvement of shuttling SR proteins, a scenario that was documented for the shuttling SR protein ASF/SF2. In cancerous cells, SRPK activity/SRp20 phosphorylation occurs at an equilibrium that facilitates IRES mediated translation. Of course it is likely that other events converging on translation machinery in transformed cells, e.g. those affecting eIF4G and its many binding partners in the translation initiation scaffold, also play a role in enabling unfettered PVSRIPO translation competence. Author Manuscript Author Manuscript Author Manuscript Author Manuscript Future perspectives To fully grasp the immunotherapeutic potential of PVSRIPO oncolysis, we have developed robust syngeneic murine models of GBM and other cancer types. These models will enable us discern how immunological events shape PVSRIPO cancer immunotherapy and to build a platform to test how PVSRIPO therapy may be broadened, enhanced or optimized. While another oncolytic PV construct was shown to produce efficacious antitumor CD8 T cell responses in a syngeneic murine cancer model, resolving issues such as: does PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/1985460 PVSRIPO oncolytic efficacy entirely rely on such responses what is the mechanism linking viral cytotoxicity and innate anti-viral immunity to the adaptive antitumor immune response are there tumor-specific or patient-speci.