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CDK2-Dependent Phosphorylation of FOXO1 as an Apoptotic Response to DNA Damage

Science, 13 October 2006
Vol. 314, Issue 5797, p. 294-297
DOI: 10.1126/science.1130512

CDK2-Dependent Phosphorylation of FOXO1 as an Apoptotic Response to DNA Damage

  1. Haojie Huang1,2,*,
  2. Kevin M. Regan1,2,
  3. Zhenkun Lou3,
  4. Junjie Chen3,
  5. Donald J. Tindall1,2,
  1. 1 Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
  2. 2 Department of Urology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
  3. 3 Department of Oncology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
  1. To whom correspondence should be addressed. E-mail: tindall.donald{at}mayo.edu
  • * Present address: University of Minnesota Cancer Center, Minneapolis, MN 55455, USA.

Abstract

The function of cyclin-dependent kinase 2 (CDK2) is often abolished after DNA damage. The inhibition of CDK2 plays a central role in DNA damage–induced cell cycle arrest and DNA repair. However, whether CDK2 also influences the survival of cells under genotoxic stress is unknown. Forkhead box O (FOXO) transcription factors are emerging as key regulators of cell survival. CDK2 specifically phosphorylated FOXO1 at serine-249 (Ser249) in vitro and in vivo. Phosphorylation of Ser249 resulted in cytoplasmic localization and inhibition of FOXO1. This phosphorylation was abrogated upon DNA damage through the cell cycle checkpoint pathway that is dependent on the protein kinases Chk1 and Chk2. Moreover, silencing of FOXO1 by small interfering RNA diminished DNA damage–induced death in both p53-deficient and p53-proficient cells. This effect was reversed by restored expression of FOXO1 in a manner depending on phosphorylation of Ser249. Functional interaction between CDK2 and FOXO1 provides a mechanism that regulates apoptotic cell death after DNA strand breakage.

    • Received for publication 26 May 2006.
    • Accepted for publication 10 August 2006.

    Citation:

    H. Huang, K. M. Regan, Z. Lou, J. Chen, and D. J. Tindall, CDK2-Dependent Phosphorylation of FOXO1 as an Apoptotic Response to DNA Damage. Science 314, 294-297 (2006).

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