Inhibitors of Cyclin-dependent Kinases Promote Survival of Post-mitotic Neuronally Differentiated PC12 Cells and Sympathetic Neurons

doi:10.1074/jbc.271.14.8161

Inhibitors of Cyclin-dependent Kinases Promote Survival of Post-mitotic Neuronally Differentiated PC12 Cells and Sympathetic Neurons (*)

From the Department of Pathology and Center for Neurobiology and Behavior, Columbia University College of Physicians and Surgeons, New York, New York 10032

^§ Supported in part by the Neurobehavioral Sciences Research Training Program of the National Institute of Mental Health and by an Aaron Diamond Foundation fellowship. To whom correspondence should be addressed:
Dept. of Pathology and Center for Neurobiology and Behavior, Columbia University College of Physicians and Surgeons, 630 W. 168th St., New York, NY 10032.
Tel.: 212-305-6370; Fax: 212-305-5498.

Abstract

Previous studies have demonstrated that multiple agents that promote survival of PC12 cells and sympathetic neurons deprived of trophic support also block cell cycle progression. Presently, we address whether inhibition of cell cycle-related cyclin-dependent kinases (CDKs) prevents neuronal cell death. We show that two distinct CDK inhibitors, flavopiridol and olomoucine, suppress the death of neuronal PC12 cells and sympathetic neurons. In addition, we demonstrate that inhibitor concentrations required to promote survival correlate with their ability to inhibit proliferation. Promotion of survival, however, does not correlate with inhibition of extracellular signal-regulated kinase or c-Jun kinase activities or with interference with the activation of c-Jun kinase that accompanies serum/nerve growth factor deprivation. In contrast to their actions on nerve growth factor-differentiated PC12 cells, the CDK inhibitors do not prevent the death of proliferation-competent PC12 cells and, in fact, promote their cell death. These findings support the hypothesis that post-mitotic neuronal cells die after removal of trophic support due to an attempt to re-enter the cell cycle in an uncoordinated and inappropriate manner. We speculate that cycling PC12 cells are not saved by these agents due to a signaling conflict between an inherent oncogenic signal and the inhibition of CDK activity.

Footnotes

↵^¶ Supported in part by a postdoctoral training grant from NCI and a national research service award from NINDS.
↵* This work was supported in part by grants from NINDS and the 3 of Dimes. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵¹ The abbreviations used are:

NGF

nerve growth factor

JNK

c-Jun kinase

GST

glutathione S-transferase

ERK

extracellular signal-regulated kinase.
↵²Orr, H. T., Clark, B., and Fedderson, R. M., Society for Neuroscience Short Course “Mitosis to Apoptosis,” Miami Beach, FL, Nov. 13, 1994 (abstr.).
↵³P. Worland, submitted for publication.
↵⁴Virdee, K., and Tolkovsky, A. M., Cold Spring Harbor Programmed Cell Death Meeting, (Cold Spring Harbor, NY, Sept. 20-24, 1995, p. 177 (abstr.).
↵⁵D. Park, unpublished observations.
- Received November 10, 1995.
- Revision received January 26, 1996.