{"doi":"10.1128/jvi.01883-14","title":"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","abstract":"<jats:title>ABSTRACT</jats:title>\n          <jats:p>\n            Protein synthesis, the most energy-consuming process in cells, responds to changing physiologic priorities, e.g., upon mitogen- or 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 p38α MAPK-interacting kinases MNK1/2 and their role in controlling 7-methyl-guanosine (m\n            <jats:sup>7</jats:sup>\n            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.\n          </jats:p>\n          <jats:p>\n            <jats:bold>IMPORTANCE</jats:bold>\n            We are targeting unfettered enterovirus IRES activity in cancer with PVSRIPO, the type 1 live-attenuated poliovirus (PV) (Sabin) vaccine containing a human rhinovirus type 2 (HRV2) IRES. A phase I clinical trial of PVSRIPO with intratumoral inoculation in patients with recurrent glioblastoma (GBM) is showing early promise. Viral translation proficiency in infected GBM cells is a core requirement for the antineoplastic efficacy of PVSRIPO. Therefore, it is critically important to understand the mechanisms controlling viral cap-independent translation in infected host cells.\n          </jats:p>","journal":"Journal of Virology","year":2014,"id":21605,"datarank":1.1864042652444717,"base_score":3.8918202981106265,"endowment":3.8918202981106265,"self_citation_contribution":0.5837730447165941,"citation_network_contribution":0.6026312205278777,"self_endowment_contribution":0.5837730447165941,"citer_contribution":0.6026312205278777,"corpus_percentile":null,"corpus_rank":null,"citation_count":48,"citer_count":22,"citers_with_citation_signal":18,"citers_with_endowment":18,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":138470,"name":"Jeffrey D. Bryant","orcid":null,"position":1,"is_corresponding":false},{"id":138347,"name":"Elena Y. Dobrikova","orcid":null,"position":2,"is_corresponding":false},{"id":138473,"name":"Mayya Shveygert","orcid":null,"position":3,"is_corresponding":false},{"id":138475,"name":"Shelton S. Bradrick","orcid":null,"position":4,"is_corresponding":false},{"id":138476,"name":"Vidyalakshmi Chandramohan","orcid":null,"position":5,"is_corresponding":false},{"id":138477,"name":"Darell D. Bigner","orcid":null,"position":6,"is_corresponding":false},{"id":138350,"name":"Matthias Gromeier","orcid":null,"position":7,"is_corresponding":false},{"id":138468,"name":"Michael C. Brown","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"base_score":3.8918202981106265,"endowment":3.8918202981106265,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"25187541","pmcid":"PMC4249076","openalex_id":"https://openalex.org/W2117566531","authors":[],"funders":[{"funder_name":"NCI NIH HHS","grant_id":"5T32CA009111","title":null},{"funder_name":"NCI NIH HHS","grant_id":"R01 CA124756","title":null},{"funder_name":"NCATS NIH HHS","grant_id":"UL1 TR001117","title":null},{"funder_name":"NCI NIH HHS","grant_id":"CA124756","title":null},{"funder_name":"NCI NIH HHS","grant_id":"P30 CA014236","title":null},{"funder_name":"NCI NIH HHS","grant_id":"T32 CA009111","title":null}],"total_grants":6,"fwci":2.4207,"citation_percentile":0.89942716,"influential_citations":4,"citation_trend":[{"year":2014,"count":1},{"year":2015,"count":4},{"year":2016,"count":2},{"year":2017,"count":5},{"year":2018,"count":11},{"year":2019,"count":3},{"year":2020,"count":4},{"year":2021,"count":3},{"year":2022,"count":7},{"year":2023,"count":4},{"year":2024,"count":1},{"year":2025,"count":2},{"year":2026,"count":1}],"oa_status":"bronze","license":"https://journals.asm.org/non-commercial-tdm-license","oa_locations":[{"url":"https://jvi.asm.org/content/jvi/88/22/13135.full.pdf","host_type":"journal"},{"url":"https://jvi.asm.org/content/jvi/88/22/13135.full.pdf","host_type":"GREEN"},{"url":"https://jvi.asm.org/content/jvi/88/22/13135.full.pdf","host_type":"publisher"},{"url":"https://journals.asm.org/doi/pdf/10.1128/JVI.01883-14","host_type":"publisher"},{"url":"https://doi.org/10.1128/jvi.01883-14","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/25187541","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/4249076","host_type":"repository"}],"fields_of_study":["Viral Infections and Immunology Research","PI3K/AKT/mTOR signaling in cancer","Virus-based gene therapy research","Biology","Medicine","Chemistry","Cell Line","Enterovirus","Gene Expression Regulation, Viral","Host-Pathogen Interactions","Humans","Intracellular Signaling Peptides and Proteins","MAP Kinase Signaling System","Protein Biosynthesis","Protein Serine-Threonine Kinases","Viral Proteins"],"mesh_terms":["Cell Line","Enterovirus","Humans","Protein Biosynthesis","Viral Proteins","Gene Expression Regulation, Viral","Protein Serine-Threonine Kinases","MAP Kinase Signaling System","Intracellular Signaling Peptides and Proteins","Host-Pathogen Interactions"],"keywords":["Internal ribosome entry site","Biology","EIF4E","Protein kinase R","Eukaryotic initiation factor","Protein kinase A","Kinase","Polypyrimidine tract-binding protein","Translation (biology)","Ribosomal s6 kinase","Guanosine","Initiation factor","Cell biology","RNA-binding protein","Cyclin-dependent kinase 2","Signal transduction","P70-S6 Kinase 1","RNA","Messenger RNA","Biochemistry","PI3K/AKT/mTOR pathway"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"gen"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-06-06T16:21:25.941227Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}