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Science 319 (5870): 1665-1668

Copyright © 2008 by the American Association for the Advancement of Science

Activation of FOXO1 by Cdk1 in Cycling Cells and Postmitotic Neurons

Zengqiang Yuan,1*{dagger} Esther B. E. Becker,1* Paola Merlo,1 Tomoko Yamada,1 Sara DiBacco,1 Yoshiyuki Konishi,1 Erik M. Schaefer,2 Azad Bonni1{ddagger}

Abstract: Activation of cyclin-dependent kinase 1 (Cdk1) has been linked to cell death of postmitotic neurons in brain development and disease. We found that Cdk1 phosphorylated the transcription factor FOXO1 at Ser249 in vitro and in vivo. The phosphorylation of FOXO1 at Ser249 disrupted FOXO1 binding with 14-3-3 proteins and thereby promoted the nuclear accumulation of FOXO1 and stimulated FOXO1-dependent transcription, leading to cell death in neurons. In proliferating cells, Cdk1 induced FOXO1 Ser249 phosphorylation at the G2/M phase of the cell cycle, resulting in FOXO1-dependent expression of the mitotic regulator Polo-like kinase (Plk). These findings define a conserved signaling link between Cdk1 and FOXO1 that may have a key role in diverse biological processes, including the degeneration of postmitotic neurons.

1 Department of Pathology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
2 Center for Signal Transduction, Cellular Analysis Business Unit/BioDiscovery Division, Invitrogen Corporation, 94 South Street, Hopkinton, MA 01748, USA.

* These authors contributed equally to this work.

{dagger} Present address: Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing 100101, China.

{ddagger} To whom correspondence should be addressed. E-mail: azad_bonni{at}

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