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Article

  • The EMBO Journal (2008) 27, 2736 - 2745
  • doi:10.1038/emboj.2008.195

Published online: 25 September 2008

Cdk5 phosphorylates Cdh1 and modulates cyclin B1 stability in excitotoxicity

Carolina Maestre1,2, Maria Delgado-Esteban2, Jose C Gomez-Sanchez3, Juan P Bolaños2 and Angeles Almeida1,2

  1. Unidad de Investigación, Hospital Universitario de Salamanca, Instituto de Estudios de Ciencias de la Salud de Castilla y León, Salamanca, Spain
  2. Departamento de Bioquímica y Biología Molecular, Instituto de Neurociencias de Castilla y León, Universidad de Salamanca, Salamanca, Spain
  3. Servicio de Neurología, Hospital Universitario de Salamanca, Salamanca, Spain

Correspondence to:

Angeles Almeida, Unidad de Investigación, Hospital Universitario de Salamanca, Paseo San Vicente 58-182, 37007 Salamanca, Spain. Tel.: +34 923 294 781; Fax: +34 923 294 579; E-mail: aaparra@usal.es

Received 23 April 2008; Accepted 29 August 2008

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.

  • Keywords:

    • apoptosis,
    • Cdh1,
    • Cdk5,
    • cyclin B1,
    • neurons