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Vol. 18, Issue 2, 404-413, February 2007

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Cdk5 Modulation of Mitogen-activated Protein Kinase Signaling Regulates Neuronal Survival

Laboratory of Neurochemistry, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892

Submitted September 22, 2006; Revised October 25, 2006; Accepted November 3, 2006
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 mitogen-activated protein kinase kinase (MEK)1 inhibits transient activation induced by nerve growth factor (NGF) in PC12 cells. To further explore the nature of this inhibition, we studied the kinetics of NGF activation of extracellular signal-regulated kinase (Erk)1/2 in cortical neurons with or without roscovitine, an inhibitor of Cdk5. NGF alone induced an Erk1/2-transient activation that peaked in 15 min and declined rapidly to baseline. Roscovitine, alone or with NGF, reached peak Erk1/2 activation in 30 min that was sustained for 48 h. Moreover, the sustained Erk1/2 activation induced apoptosis in cortical neurons. Significantly, pharmacological application of the MEK1 inhibitor PD98095 to roscovitine-treated cortical neurons prevented apoptosis. These results were also confirmed by knocking down Cdk5 activity in cortical neurons with Cdk5 small interference RNA. 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 mitogen-activated protein kinase signaling pathway.

Address correspondence to: Harish C. Pant (panth{at}ninds.nih.gov)

Abbreviations used: Cdk5, cyclin-dependent kinase-5; Erk, extracellular signal-regulated protein kinase; MAPK, mitogen-activated protein kinase; MEK1, mitogen-activated protein kinase kinase 1; NGF, nerve growth factor; TUNEL, terminal deoxynucleotidyl-transferase enzyme-mediated dUTP nick end labeling; PI3K, phosphatidylinositol 3-kinase; siRNA, small interference RNA.