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Cyclin-dependent kinases participate in death of neurons evoked by DNA-damaging agents
D S Park1, E J Morris, J Padmanabhan
1Department of Pathology and Center for Neurobiology and Behavior, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA. dpark@uottawa.ca
Abstract:
Previous reports have indicated that DNA-damaging treatments including certain anticancer therapeutics cause death of postmitotic nerve cells both in vitro and in vivo. Accordingly, it has become important to understand the signaling events that control this process. We recently hypothesized that certain cell cycle molecules may play an important role in neuronal death signaling evoked by DNA damage. Consequently, we examined whether cyclin-dependent kinase inhibitors (CKIs) and dominant-negative (DN) cyclin-dependent kinases (CDK) protect sympathetic and cortical neurons against DNA-damaging conditions. We show that Sindbis virus-induced expression of CKIs p16(ink4), p21(waf/cip1), and p27(kip1), as well as DN-Cdk4 and 6, but not DN-Cdk2 or 3, protect sympathetic neurons against UV irradiation- and AraC-induced death. We also demonstrate that the CKIs p16 and p27 as well as DN-Cdk4 and 6 but not DN-Cdk2 or 3 protect cortical neurons from the DNA damaging agent camptothecin. Finally, in consonance with our hypothesis and these results, cyclin D1-associated kinase activity is rapidly and highly elevated in cortical neurons upon camptothecin treatment. These results suggest that postmitotic neurons may utilize Cdk4 and 6, signals that normally control proliferation, to mediate death signaling resulting from DNA-damaging conditions.
Insights
DNA-damaging agents can kill nerve cells. Cyclin-dependent kinase inhibitors (CKIs) and specific dominant-negative cyclin-dependent kinases (CDKs) protect neurons from this death, suggesting a role for cell cycle regulators in neuronal survival.
Area of Science:
- Neuroscience
- Cell Biology
- Molecular Biology
Background:
- DNA-damaging treatments, including anticancer drugs, can cause postmitotic neuronal death.
- Understanding the signaling pathways involved in this neuronal death is crucial.
Purpose of the Study:
- To investigate the role of cell cycle molecules in DNA damage-induced neuronal death.
- To determine if cyclin-dependent kinase inhibitors (CKIs) and dominant-negative (DN) cyclin-dependent kinases (CDKs) protect neurons.
Main Methods:
- Sindbis virus-induced expression of CKIs (p16, p21, p27) and DN-CDKs (Cdk4, Cdk6, Cdk2, Cdk3) in sympathetic and cortical neurons.
- Exposure of neurons to DNA-damaging agents (UV irradiation, AraC, camptothecin).
- Assessment of neuronal survival and cyclin D1-associated kinase activity.
Main Results:
- CKIs p16, p21, and p27, along with DN-Cdk4 and DN-Cdk6, protected sympathetic neurons from UV and AraC-induced death.
- CKIs p16 and p27, and DN-Cdk4 and DN-Cdk6, protected cortical neurons from camptothecin-induced death.
- Cyclin D1-associated kinase activity was significantly elevated in cortical neurons treated with camptothecin.
Conclusions:
- Postmitotic neurons may employ cell cycle regulators, specifically Cdk4 and Cdk6, to mediate death signaling in response to DNA damage.
- These findings suggest potential therapeutic targets for protecting neurons from DNA damage-induced death.