Cdk5 phosphorylates Cdh1 and modulates cyclin B1 stability in excitotoxicity.
Anaphase-promoting complex/cyclosome (APC/C), an E3 ubiquitin ligase that destabilizes cell cycle proteins, is activated by Cdh1 in post-mitotic neurons, where it regulates axonal growth, synaptic plasticity and survival. The APC/C-Cdh1 substrate, cyclin B1, has been found to accumulate in degenerating brain areas in Alzheimer's disease and stroke. This highlights the importance of elucidating cyclin B1 regulation by APC/C-Cdh1 in neurons under stress conditions relevant to neurological disease. Here, we report that stimulation of N-methyl-D-aspartate receptors (NMDARs) that occurs in neurodegenerative diseases promoted the accumulation of cyclin B1 in the nuclei of cortical neurons; this led the neurons to undergo apoptotic death. Moreover, we found that the Ser-40, Thr-121 and Ser-163 triple phosphorylation of Cdh1 by the cyclin-dependent kinase-5 (Cdk5)-p25 complex was necessary and sufficient for cyclin B1 stabilization and apoptotic death after NMDAR stimulation. These results reveal Cdh1 as a novel Cdk5 substrate that mediates cyclin B1 neuronal accumulation in excitotoxicity.
Maestre
Carolina
C
Unidad de Investigación, Hospital Universitario de Salamanca, Instituto de Estudios de Ciencias de la Salud de Castilla y León, Salamanca, Spain.
Delgado-Esteban
Maria
M
Gomez-Sanchez
Jose C
JC
Bolaños
Juan P
JP
Almeida
Angeles
A
D000818:Animals; D017209:Apoptosis; D015820:Cadherins / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D019926:Cyclin B / Q000378:metabolism*; D056744:Cyclin B1; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012694:Serine / Q000737:chemistry
D015820:Cadherins; C534701:Ccnb1 protein, rat; D019926:Cyclin B; D056744:Cyclin B1; D016194:Receptors, N-Methyl-D-Aspartate; D012694:Serine; D051360:Cyclin-Dependent Kinase 5