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Pim-1 kinase as activator of the cell cycle pathway in neuronal death induced by DNA damage
- Source :
- Journal of neurochemistry. 112(2)
- Publication Year :
- 2009
-
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.
- Subjects :
- Programmed cell death
CDC25A
Chromatin Immunoprecipitation
Time Factors
DNA damage
Green Fluorescent Proteins
Transfection
Biochemistry
Cellular and Molecular Neuroscience
Mice
Adenosine Triphosphate
Proto-Oncogene Proteins c-pim-1
Cyclin-dependent kinase
Sulfur Isotopes
Animals
Humans
cdc25 Phosphatases
CHEK1
RNA, Messenger
Kinase activity
Enzyme Inhibitors
RNA, Small Interfering
Cell Line, Transformed
Cerebral Cortex
Mice, Knockout
Neurons
biology
Cell Death
Kinase
Cell Cycle
NF-kappa B
Cell cycle
Embryo, Mammalian
Staurosporine
Cell biology
Up-Regulation
biology.protein
Camptothecin
DNA Damage
Subjects
Details
- ISSN :
- 14714159
- Volume :
- 112
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- Journal of neurochemistry
- Accession number :
- edsair.doi.dedup.....3026f4a942bb098ba0125123fe848afb