Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

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}hms.harvard.edu


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Troxerutin Counteracts Domoic Acid-Induced Memory Deficits in Mice by Inhibiting CCAAT/Enhancer Binding Protein {beta}-Mediated Inflammatory Response and Oxidative Stress.
J. Lu, D.-m. Wu, Y.-l. Zheng, B. Hu, W. Cheng, Z.-f. Zhang, and M.-q. Li (2013)
J. Immunol. 190, 3466-3479
   Abstract »    Full Text »    PDF »
Sumoylated MEF2A Coordinately Eliminates Orphan Presynaptic Sites and Promotes Maturation of Presynaptic Boutons.
T. Yamada, Y. Yang, J. Huang, G. Coppola, D. H. Geschwind, and A. Bonni (2013)
J. Neurosci. 33, 4726-4740
   Abstract »    Full Text »    PDF »
ER stress potentiates insulin resistance through PERK-mediated FOXO phosphorylation.
W. Zhang, V. Hietakangas, S. Wee, S. C. Lim, J. Gunaratne, and S. M. Cohen (2013)
Genes & Dev. 27, 441-449
   Abstract »    Full Text »    PDF »
Post-translational regulation of FOXO.
Q. Xie, J. Chen, and Z. Yuan (2012)
Acta Biochim Biophys Sin 44, 897-901
   Abstract »    Full Text »    PDF »
Deregulated Cdk5 triggers aberrant activation of cell cycle kinases and phosphatases inducing neuronal death.
K.-H. Chang, F. Vincent, and K. Shah (2012)
J. Cell Sci. 125, 5124-5137
   Abstract »    Full Text »    PDF »
14-3-3{zeta}, a Novel Androgen-Responsive Gene, Is Upregulated in Prostate Cancer and Promotes Prostate Cancer Cell Proliferation and Survival.
T. Murata, K.-i. Takayama, T. Urano, T. Fujimura, D. Ashikari, D. Obinata, K. Horie-Inoue, S. Takahashi, Y. Ouchi, Y. Homma, et al. (2012)
Clin. Cancer Res. 18, 5617-5627
   Abstract »    Full Text »    PDF »
Applications of post-translational modifications of FoxO family proteins in biological functions.
Y. Zhao, Y. Wang, and W.-G. Zhu (2011)
J Mol Cell Biol 3, 276-282
   Abstract »    Full Text »    PDF »
Cdc25A Regulates Matrix Metalloprotease 1 through Foxo1 and Mediates Metastasis of Breast Cancer Cells.
X. Feng, Z. Wu, Y. Wu, W. Hankey, T. W. Prior, L. Li, R. K. Ganju, R. Shen, and X. Zou (2011)
Mol. Cell. Biol. 31, 3457-3471
   Abstract »    Full Text »    PDF »
Egr-1 Transactivates Bim Gene Expression to Promote Neuronal Apoptosis.
B. Xie, C. Wang, Z. Zheng, B. Song, C. Ma, G. Thiel, and M. Li (2011)
J. Neurosci. 31, 5032-5044
   Abstract »    Full Text »    PDF »
JNK regulates FoxO-dependent autophagy in neurons.
P. Xu, M. Das, J. Reilly, and R. J. Davis (2011)
Genes & Dev. 25, 310-322
   Abstract »    Full Text »    PDF »
Global gene expression profiling of somatic motor neuron populations with different vulnerability identify molecules and pathways of degeneration and protection.
E. Hedlund, M. Karlsson, T. Osborn, W. Ludwig, and O. Isacson (2010)
Brain 133, 2313-2330
   Abstract »    Full Text »    PDF »
A FOXO-Pak1 transcriptional pathway controls neuronal polarity.
L. de la Torre-Ubieta, B. Gaudilliere, Y. Yang, Y. Ikeuchi, T. Yamada, S. DiBacco, J. Stegmuller, U. Schuller, D. A. Salih, D. Rowitch, et al. (2010)
Genes & Dev. 24, 799-813
   Abstract »    Full Text »    PDF »
c-Jun N-terminal Kinase Enhances MST1-mediated Pro-apoptotic Signaling through Phosphorylation at Serine 82.
W. Bi, L. Xiao, Y. Jia, J. Wu, Q. Xie, J. Ren, G. Ji, and Z. Yuan (2010)
J. Biol. Chem. 285, 6259-6264
   Abstract »    Full Text »    PDF »
Differential Response of Glioma Cells to FOXO1-Directed Therapy.
C. J. Lau, Z. Koty, and J. Nalbantoglu (2009)
Cancer Res. 69, 5433-5440
   Abstract »    Full Text »    PDF »
Regulation of Neuronal Cell Death by MST1-FOXO1 Signaling.
Z. Yuan, M. K. Lehtinen, P. Merlo, J. Villen, S. Gygi, and A. Bonni (2009)
J. Biol. Chem. 284, 11285-11292
   Abstract »    Full Text »    PDF »
Cdk5 phosphorylates Cdh1 and modulates cyclin B1 stability in excitotoxicity.
C. Maestre, M. Delgado-Esteban, J. C. Gomez-Sanchez, J. P. Bolanos, and A. Almeida (2008)
EMBO J. 27, 2736-2745
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882