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.
CDK2-Dependent Phosphorylation of FOXO1 as an Apoptotic Response to DNA Damage
Haojie Huang,1,2*Kevin M. Regan,1,2Zhenkun Lou,3Junjie Chen,3Donald J. Tindall1,2
The function of cyclin-dependent kinase 2 (CDK2) is often abolishedafter DNA damage. The inhibition of CDK2 plays a central rolein DNA damage–induced cell cycle arrest and DNA repair.However, whether CDK2 also influences the survival of cellsunder genotoxic stress is unknown. Forkhead box O (FOXO) transcriptionfactors are emerging as key regulators of cell survival. CDK2specifically phosphorylated FOXO1 at serine-249 (Ser249) invitro and in vivo. Phosphorylation of Ser249 resulted in cytoplasmiclocalization and inhibition of FOXO1. This phosphorylation wasabrogated upon DNA damage through the cell cycle checkpointpathway that is dependent on the protein kinases Chk1 and Chk2.Moreover, silencing of FOXO1 by small interfering RNA diminishedDNA damage–induced death in both p53-deficient and p53-proficientcells. This effect was reversed by restored expression of FOXO1in a manner depending on phosphorylation of Ser249. Functionalinteraction between CDK2 and FOXO1 provides a mechanism thatregulates apoptotic cell death after DNA strand breakage.
1 Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. 2 Department of Urology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. 3 Department of Oncology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
* Present address: University of Minnesota Cancer Center, Minneapolis,MN 55455, USA.
To whom correspondence should be addressed. E-mail: tindall.donald{at}mayo.edu
The editors suggest the following Related Resources on Science sites:
In Science Magazine
PERSPECTIVES
Jiri Bartek and Jiri Lukas (13 October 2006) Science314 (5797), 261.
[DOI: 10.1126/science.1133758] |Summary »|Full Text »|PDF »
In Science Signaling
EDITORS' CHOICE
L. Bryan Ray (17 October 2006) Sci. STKE2006 (357), tw359.
[DOI: 10.1126/stke.3572006tw359] |Abstract »
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Activation of FOXO1 by Cdk1 in Cycling Cells and Postmitotic Neurons.
Z. Yuan, E. B. E. Becker, P. Merlo, T. Yamada, S. DiBacco, Y. Konishi, E. M. Schaefer, and A. Bonni (2008)
Science
319, 1665-1668
|Abstract »|Full Text »|PDF »
Transcription Factor FOXO3a Mediates Apoptosis in HIV-1-Infected Macrophages.
A Novel Role for p73 in the Regulation of Akt-Foxo1a-Bim Signaling and Apoptosis Induced by the Plant Lectin, Concanavalin A.
A.R.M. R. Amin, R. K. Paul, V. S. Thakur, and M. L. Agarwal (2007)
Cancer Res.
67, 5617-5621
|Abstract »|Full Text »|PDF »
ATM and ATR Substrate Analysis Reveals Extensive Protein Networks Responsive to DNA Damage.
S. Matsuoka, B. A. Ballif, A. Smogorzewska, E. R. McDonald III, K. E. Hurov, J. Luo, C. E. Bakalarski, Z. Zhao, N. Solimini, Y. Lerenthal, et al. (2007)
Science
316, 1160-1166
|Abstract »|Full Text »|PDF »
Interaction of a Cyclin E Fragment with Ku70 Regulates Bax-Mediated Apoptosis.
S. Mazumder, D. Plesca, M. Kinter, and A. Almasan (2007)
Mol. Cell. Biol.
27, 3511-3520
|Abstract »|Full Text »|PDF »
To whom correspondence should be addressed. E-mail: 
