Activation of FOXO1 by Cdk1 in cycling cells and postmitotic neurons

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 Ser(249) in vitro and in vivo. The phosphorylation of FOXO1 at Ser(249) 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 Ser(249) phosphorylation at the G(2)/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.