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 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.
Yuan
Zengqiang
Z
Department of Pathology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
Becker
Esther B E
EB
Merlo
Paola
P
Yamada
Tomoko
T
DiBacco
Sara
S
Konishi
Yoshiyuki
Y
Schaefer
Erik M
EM
Bonni
Azad
A
D048948:14-3-3 Proteins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D016203:CDC2 Protein Kinase / Q000378:metabolism*; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D000097869:Polo-Like Kinase 1
D048948:14-3-3 Proteins; D016203:CDC2 Protein Kinase; D018797:Cell Cycle Proteins; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D009419:Nerve Tissue Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D012694:Serine; D000097869:Polo-Like Kinase 1; C085126:FOXO1 protein, human; C467200:Foxo1 protein, mouse; C074639:Foxo1 protein, rat