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.

ABSTRACT: 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 cerebr

SUBMITTER: Sun KH 

PROVIDER: S-EPMC2770948 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature