| Autor: |
Maestre C; Unidad de Investigación, Hospital Universitario de Salamanca, Instituto de Estudios de Ciencias de la Salud de Castilla y León, Salamanca, Spain., Delgado-Esteban M, Gomez-Sanchez JC, Bolaños JP, Almeida A |
| Jazyk: |
angličtina |
| Zdroj: |
The EMBO journal [EMBO J] 2008 Oct 22; Vol. 27 (20), pp. 2736-45. Date of Electronic Publication: 2008 Sep 25. |
| DOI: |
10.1038/emboj.2008.195 |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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