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Volume 17, Number 23,
Issue of December 1, 1997
pp. 8975-8983
Cyclin Dependent Kinase Inhibitors and Dominant Negative Cyclin
Dependent Kinase 4 and 6 Promote Survival of NGF-Deprived Sympathetic
Neurons
Received June 26, 1997; revised Aug. 27, 1997; accepted Sept. 16, 1997.
David S. Park1,
Beth Levine2,
Giovanna Ferrari3, and
Lloyd A. Greene1
1 Department of Pathology and Center for Neurobiology
and Behavior and 2 Department of Medicine, Columbia
University College of Physicians and Surgeons, New York, New York
10032, and 3 Fidia SPA in AS 35031 Abano Terme-Via Ponte
Della, Italy
Neuronal apoptosis plays a critical role in both normal development
and disease. However, the precise molecular events controlling neuronal
apoptosis are not well understood. Previously, we hypothesized that
cell cycle regulatory molecules function in controlling the apoptotic
pathways of trophic factor-deprived neurons. To test this hypothesis,
we used the RNA alphavirus Sindbis to express three known cyclin
dependent kinase inhibitors (CKIs), p16ink4,
p21waf/cip, and p27kip1, and
dominant negative mutant forms of four known G1 cyclin
dependent kinases (CDKs), Cdk2, Cdk3, Cdk4, and Cdk6, in primary
cultured rat superior cervical ganglion sympathetic neurons. We
demonstrate that expression of each of the CKIs protects the
postmitotic cultured neurons from apoptotic death evoked by withdrawal
of NGF. In addition, we show that expression of dominant negative forms
of Cdk4 or Cdk6, but not Cdk2 or Cdk3, protects NGF-deprived
sympathetic neurons from death. Such findings suggest the participation
of several CDKs and their cognate cyclins in a neuronal apoptotic pathway.
Key words:
apoptosis;
CDK;
sympathetic neuron;
Sindbis;
cell cycle;
cell death
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