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© The Rockefeller University Press, 0021-9525/1998//457 $5.00
The Journal of Cell Biology, Volume 143, Number 2, , 1998 457-467

Cyclin-dependent Kinases Participate in Death of Neurons Evoked by DNA-damaging Agents

David S. Park^*, Erick J. Morris, Jaya Padmanabhan^*, Michael L. Shelanski^*, Herbert M. Geller, and Lloyd A. Greene^*

^* Department of Pathology and Center for Neurobiology and Behavior, Columbia University College of Physicians and Surgeons, New York, New York 10032; and Department of Pharmacology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854

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.

Key Words: apoptosis • CDK • neuronal • cell cycle • DNA damage

Abbreviations used in this paper: AraC, cytosine arabinoside; CAT, chloramphenicol acetyl transferase; CDK, cyclin-dependent kinase; CKI, cyclin-dependent kinase inhibitor; CNS, central nervous system; DN, dominant-negative; pRB, retinoblastoma protein.

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