Cdk5 Levels Oscillate during the Neuronal Cell Cycle Cdh1 UBIQUITINATION TRIGGERS PROTEOSOME-DEPENDENT DEGRADATION DURING S-PHASE

Jie Zhang; Huifang Li; Tingwen Zhou; Jiechao Zhou; Karl Herrup

doi:10.1074/jbc.M112.343152

Cdk5 Levels Oscillate during the Neuronal Cell Cycle

Cdh1 UBIQUITINATION TRIGGERS PROTEOSOME-DEPENDENT DEGRADATION DURING S-PHASE*

From the ^‡Institute of Neuroscience, Xiamen University, Xiamen, Fujian, China 361005 and
the ^§Department of Cell Biology and Neuroscience, Rutgers University, 604 Allison Road, Piscataway, New Jersey 08854

↵1 To whom correspondence may be addressed: Institute of Neuroscience, Xiamen University, SiMing NanLu 422, Xiamen, Fujian, China, 361005. Tel.: 086-592-2180717; Fax: 086-592-2180717; E-mail: jiezhang{at}xmu.edu.cn.
↵2 To whom correspondence may be addressed: Department of Cell Biology and Neuroscience, Rutgers University, 604 Allison Road, Piscataway, New Jersey 08854. E-mail: herrup{at}biology.rutgers.edu.

Background: Cdk5 is an atypical Cdk that inhibits the cell cycle in post-mitotic neurons.

Results: APC-Cdh1 mediates the degradation of Cdk5 during S phase of the cell cycle.

Conclusion: Maintenance of the proper levels and nuclear location of Cdk5 act to suppress the cell cycle in neuronal cells.

Significance: Subcellular localization of Cdk5 and p35 may play roles in the pathogenesis of Alzheimer disease.

Abstract

When cell cycle re-activation occurs in post-mitotic neurons it places them at increased risk for death. The cell cycle/cell death association has been reported in many neurodegenerative diseases including Alzheimer disease (AD), yet the mechanisms by which a normal neuron suppresses the cycle remain largely unknown. Recently, our laboratory has shown that Cdk5 (cyclin-dependent kinase 5) is a key player in this protective function. When a neuron is under stress, Cdk5 is transported to the cytoplasm; this eliminates its cell cycle suppression activity and the neuron re-enters S-phase. In the current study we show that a similar principle applies during a normal cell cycle. When a neuronal cell enters S phase, Cdk5 is transported to the cytoplasm where it is ubiquitinated by the E3 ligase APC-Cdh1. Ubiquitinated Cdk5 is then rapidly degraded by the proteasome. The ubiquitination site of Cdk5 appears to be in the p35 binding area; in the presence of high levels of p35, the ubiquitination of Cdk5 was blocked, and the degradation in S phase was attenuated. The data suggest an unsuspected role for Cdk5 during the progression of a normal cell cycle and offer new pharmaceutical targets for regulating neuronal cell cycling and cell death.

Footnotes

↵* This work was supported, in whole or in part, by National Institutes of Health Grant NS20591 and Rutgers University.
↵ This article contains supplemental Fig. S1.