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Vol. 20, Issue 21, 4611-4619, November 1, 2009

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Direct and Indirect Roles of Cyclin-dependent Kinase 5 as an Upstream Regulator in the c-Jun NH₂-Terminal Kinase Cascade: Relevance to Neurotoxic Insults in Alzheimer's Disease

Kai-Hui Sun^*, Hyoung-gon Lee, Mark A. Smith, and Kavita Shah^*

*Department of Chemistry and Purdue Center for Cancer Research, Purdue University, West Lafayette, IN 47907; and Department of Pathology, Case Western Reserve University, Cleveland, OH 44106

Submitted May 28, 2009; Revised September 3, 2009; Accepted September 15, 2009
Monitoring Editor: Donald D. Newmeyer

Significant increase in JNK, c-Jun, and Cdk5 activities are reported in Alzheimer's disease (AD). Inhibition of c-Jun prevents neuronal cell death in in vivo AD models, highlighting it as a major JNK effector. Both JNK and Cdk5 promote neurodegeneration upon deregulation; however, Cdk5 has not been mechanistically linked to JNK or c-Jun. This study presents the first mechanism showing Cdk5 as a major regulator of the JNK cascade. Deregulated Cdk5 induces biphasic activation of JNK pathway. The first phase revealed c-Jun as a direct substrate of Cdk5, whose activation is independent of reactive oxygen species (ROS) and JNK. In the second phase, Cdk5 activates c-Jun via ROS-mediated activation of JNK. Rapid c-Jun activation is supported by in vivo data showing c-Jun phosphorylation in cerebral cortex upon p25 induction in transgenic mice. Cdk5-mediated biphasic activation of c-Jun highlights c-Jun, rather than JNK, as an important therapeutic target, which was confirmed in neuronal cells. Finally, Cdk5 inhibition endows superior protection against neurotoxicity, suggesting that Cdk5 is a preferable therapeutic target for AD relative to JNK and c-Jun.

Address correspondence to: Kavita Shah (shah23{at}purdue.edu).