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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.

Original publication

DOI

10.1126/science.1152337

Type

Journal article

Journal

Science

Publication Date

21/03/2008

Volume

319

Pages

1665 - 1668

Keywords

14-3-3 Proteins, Animals, Apoptosis, CDC2 Protein Kinase, Cell Cycle, Cell Cycle Proteins, Cell Line, Tumor, Cell Nucleus, Cell Proliferation, Cells, Cultured, Forkhead Box Protein O1, Forkhead Transcription Factors, Humans, Mice, NIH 3T3 Cells, Nerve Tissue Proteins, Neurons, Phosphorylation, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, Rats, Serine, Signal Transduction, Transcription, Genetic