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 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.

journal_name

Mol Biol Cell

authors

Sun KH,Lee HG,Smith MA,Shah K

doi

10.1091/mbc.e09-05-0433

subject

Has Abstract

pub_date

2009-11-01 00:00:00

pages

4611-9

issue

21

eissn

1059-1524

issn

1939-4586

pii

E09-05-0433

journal_volume

20

pub_type

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