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‐κB) pathway as Pim‐1 expression and activity are significantly blocked by siRNA‐mediated knockdown of NF‐κB or NF‐κB 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.

DJ-1 Interacts with and Regulates Paraoxonase-2, an Enzyme Critical for Neuronal Survival in Response to Oxidative Stress

“…Cortical neuron cultures were prepared as described before [41], [42]. Briefly, embryos were extracted at 14.5–15.5 days gestation.…”

Regulation of Ischemic Neuronal Death by E2F4-p130 Protein Complexes

“…ChIP Assay-CGNs treated with/without hypoxia and reoxygenation were subjected to a ChIP assay as described previously (33). The mouse B-Myb promoter region was amplified using the following primers: 5Ј-CCTCCTCCTTC-TCCTCCTTC-3Ј and 5-CACTATACCCGTGCGCTTCT-3Ј.…”

“…Mediated by Genotoxic Stress-Aberrant activation of neuronal cell cycle induced by pathologic stress such as DNA damage and ischemic insult is thought to contribute to cell death through regulation of E2F members (7,17,33). However, the relative contribution of different E2F members in neuronal death is not clear.…”

Role for DNA Damage Signaling in Pulmonary Arterial Hypertension

“…In line with our findings, studies in hematopoietic cells and neurons have shown a significant increase in Pim-1 in response to DNA damage contributing to cell survival. 43,44 In addition to miR-204 downregulation, upregulation of Pim-1 in PAH 10 could contribute to the PARP-1-dependent cell survival in PAH-PASMCs. In addition, several recent studies have attributed numerous posttranscriptional functions to PARP proteins, 19 including the regulation of the microRNA binding protein Argonaute 2.…”