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: 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(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.
  
  
  OBJECTIVE
  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.
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, USA Department of Surgery, Division of Neurosurgery, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Brown
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, USA Department of Surgery, Division of Neurosurgery, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Bryant
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, USA Department of Surgery, Division of Neurosurgery, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Elena Y
authors.initials: EY
authors.lastname: Dobrikova
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, USA Department of Surgery, Division of Neurosurgery, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Mayya
authors.initials: M
authors.lastname: Shveygert
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Shelton S
authors.initials: SS
authors.lastname: Bradrick
authors.affiliation: Department of Surgery, Division of Neurosurgery, Duke University Medical Center, Durham, North Carolina, USA Department of Pathology, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Vidyalakshmi
authors.initials: V
authors.lastname: Chandramohan
authors.affiliation: Department of Surgery, Division of Neurosurgery, Duke University Medical Center, Durham, North Carolina, USA Department of Pathology, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Darell D
authors.initials: DD
authors.lastname: Bigner
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, USA Department of Surgery, Division of Neurosurgery, Duke University Medical Center, Durham, North Carolina, USA grome001@mc.duke.edu.
authors.forename: Matthias
authors.initials: M
authors.lastname: Gromeier
mesh_terms: D002460:Cell Line; D004770:Enterovirus / Q000235:genetics*; D015967:Gene Expression Regulation, Viral; D054884:Host-Pathogen Interactions; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D014764:Viral Proteins / Q000096:biosynthesis*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D014764:Viral Proteins; C491395:MKNK1 protein, human; C087728:SRPK1 protein, human; C486342:MKNK2 protein, human; D017346:Protein Serine-Threonine Kinases