title: Pim-1 kinase as activator of the cell cycle pathway in neuronal death induced by DNA damage.
abstract: DNA damage is a critical component of neuronal death underlying neurodegenerative diseases and injury. Neuronal death evoked by DNA damage is characterized by inappropriate activation of multiple cell cycle components. However, the mechanism regulating this activation is not fully understood. We demonstrated previously that the cell division cycle (Cdc) 25A phosphatase mediates the activation of cyclin-dependent kinases and neuronal death evoked by the DNA damaging agent camptothecin. We also showed that Cdc25A activation is blocked by constitutive checkpoint kinase 1 activity under basal conditions in neurons. Presently, we report that an additional factor is central to regulation of Cdc25A phosphatase in neuronal death. In a gene array screen, we first identified Pim-1 as a potential factor up-regulated following DNA damage. We confirmed the up-regulation of Pim-1 transcript, protein and kinase activity following DNA damage. This induction of Pim-1 is regulated by the nuclear factor kappa beta (NF-kappaB) pathway as Pim-1 expression and activity are significantly blocked by siRNA-mediated knockdown of NF-kappaB or NF-kappaB pharmacological inhibitors. Importantly, Pim-1 activity is critical for neuronal death in this paradigm and its deficiency blocks camptothecin-mediated neuronal death. It does so by activating Cdc25A with consequent activation of cyclin D1-associated kinases. Taken together, our results demonstrate that Pim-1 kinase plays a central role in DNA damage-evoked neuronal death by regulating aberrant neuronal cell cycle activation.
authors.affiliation: Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Mohammad
authors.initials: M
authors.lastname: Parsanejad
authors.forename: En
authors.initials: E
authors.lastname: Huang
authors.forename: Dianbo
authors.initials: D
authors.lastname: Qu
authors.forename: Hossein
authors.initials: H
authors.lastname: Aleyasin
authors.forename: Maxime W C
authors.initials: MW
authors.lastname: Rousseaux
authors.forename: Yasmilde Rodriguez
authors.initials: YR
authors.lastname: Gonzalez
authors.forename: Sean P
authors.initials: SP
authors.lastname: Cregan
authors.forename: Ruth S
authors.initials: RS
authors.lastname: Slack
authors.forename: David S
authors.initials: DS
authors.lastname: Park
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002166:Camptothecin / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002461:Cell Line, Transformed; D002540:Cerebral Cortex / Q000166:cytology; D047369:Chromatin Immunoprecipitation / Q000379:methods; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology*; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D051573:Proto-Oncogene Proteins c-pim-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D019311:Staurosporine / Q000494:pharmacology; D013460:Sulfur Isotopes / Q000378:metabolism; D013997:Time Factors; D014162:Transfection / Q000379:methods; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D020687:cdc25 Phosphatases / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D016328:NF-kappa B; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D013460:Sulfur Isotopes; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D000255:Adenosine Triphosphate; D051573:Proto-Oncogene Proteins c-pim-1; D020687:cdc25 Phosphatases; D019311:Staurosporine; D002166:Camptothecin