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A more recent version of this article appeared on February 1, 2007
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Submitted on September 22, 2006
Revised on October 25, 2006
Accepted on November 3, 2006
Laboratory of Neurochemistry, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892
Monitoring Editor: M. Bishr Omary
Cdk5, a cyclin-dependent kinase, is critical for neuronal development, neuronal migration, cortical lamination and survival. Its survival role is based, in part, on "cross-talk" interactions with apoptotic and survival signaling pathways. Previously, we showed that Cdk5 phosphorylation of MEK1 inhibits transient activation induced by NGF in PC12 cells. To further explore the nature of this inhibition, we studied the kinetics of nerve growth factor (NGF) activation of Erk1/2 in cortical neurons with or without roscovitine, an inhibitor of Cdk5. NGF alone induced an Erk1/2 transient activation that peaked in 15 mins and declined rapidly to baseline. Roscovitine, alone or with NGF, reached peak Erk1/2 activation in 30 mins that was sustained for 48 h. Moreover, the sustained Erk1/2 activation induced apoptosis in cortical neurons. Significantly, pharmacologic application of the MEK1 inhibitor, PD 98095 to roscovitine-treated cortical neurons prevented apoptosis. These results were also confirmed by knocking down Cdk5 activity in cortical neurons with Cdk5 siRNA. Apoptosis was correlated with a significant shift of phosphorylated tau and neurofilaments from axons to neuronal cell bodies. These results suggest that survival of cortical neurons is also dependent on tight Cdk5 modulation of the MAPK signaling pathway.
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