Cdk5 levels oscillate during the neuronal cell cycle: Cdh1 ubiquitination triggers proteosome-dependent degradation during S-phase.
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.
Institute of Neuroscience, Xiamen University, Xiamen, Fujian, China. jiezhang@xmu.edu.cn
Jie
J
Zhang
Huifang
H
Li
Tingwen
T
Zhou
Jiechao
J
Zhou
Karl
K
Herrup
D000818:Animals; D064200:Cdh1 Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002467:Cell Nucleus / Q000201:enzymology; D002478:Cells, Cultured; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D004795:Enzyme Stability; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000201:enzymology* / Q000502:physiology; D010446:Peptide Fragments / Q000378:metabolism; D010770:Phosphotransferases / Q000378:metabolism; D061251:Primary Cell Culture; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D059748:Proteolysis; D059807:S Phase Cell Cycle Checkpoints; D054875:Ubiquitination
D064200:Cdh1 Proteins; C492236:Cdk5r1 protein, mouse; D018797:Cell Cycle Proteins; C577585:Fzr1 protein, mouse; D010446:Peptide Fragments; D010770:Phosphotransferases; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse; D046988:Proteasome Endopeptidase Complex