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The Journal of Neuroscience, October 15, 1999, 19(20):8747-8756
Role of Cell Cycle Regulatory Proteins in Cerebellar Granule
Neuron Apoptosis
Jaya
Padmanabhan,
David S.
Park,
Lloyd A.
Greene, and
Michael L.
Shelanski
Department of Pathology and Center for Neurobiology and Behavior,
Taub Center for Alzheimer's Disease Research, College of Physicians
and Surgeons, Columbia University, New York, New York 10032
Cerebellar granule neurons (CGNs) undergo apoptosis when deprived
of depolarizing concentrations of KCl, but the underlying molecular
mechanisms are not yet clear. Although caspases have been postulated to
be involved in CGN cell death, inhibitors of caspases failed to prevent
apoptosis under our culture conditions, suggesting an involvement of
other molecules and pathways. We find that inhibitors of
cyclin-dependent kinases flavopiridol, olomoucine, and
roscovitineprotect CGNs from KCl withdrawal-induced apoptosis,
suggesting that cell cycle components play a significant role in the
death of these neurons. Analysis of the different cell cycle regulatory
elements in this model revealed that apoptosis is preceded by an
increase in the level of cyclin E protein, with elevated nuclear levels
of cyclin D1 and with enhanced activity of the cyclin D1- and E-
associated kinases. In addition, there was a significant decrease in
the level of the cyclin-dependent kinase (cdk) inhibitor p27. In
agreement with these changes, analysis of a major substrate of
cyclin-activated cdks, retinoblastoma protein (Rb), showed an increase
in the level of phosphorylated forms within 1 hr of KCl withdrawal.
Moreover, the overall levels of Rb protein were significantly reduced
within 6-12 hr of KCl withdrawal and did so by a caspase-independent
mechanism. All of these responses were blocked by cdk inhibitors. These
findings indicate that cdks act at an early step in the pathway by
which KCl withdrawal induces apoptotic death of cerebellar granule
cells and suggest that additional elements of the cell cycle machinery participate in this mechanism.
Key words:
neurons; apoptosis; cell cycle; cyclins; cdk; Rb; CKI
Copyright © 1999 Society for Neuroscience 0270-6474/99/19208747-10$05.00/0
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