CDK2-dependent phosphorylation of FOXO1 as an apoptotic response to DNA damage.
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.
Huang
Haojie
H
Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Regan
Kevin M
KM
Lou
Zhenkun
Z
Chen
Junjie
J
Tindall
Donald J
DJ
D000818:Animals; D017209:Apoptosis; D002166:Camptothecin / Q000494:pharmacology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D000071877:Checkpoint Kinase 1; D064447:Checkpoint Kinase 2; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D004249:DNA Damage; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53; D010768:Phosphoserine; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C000605867:CHEK1 protein, human; C578634:CHEK2 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; C578633:Chek2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051357:Cyclin-Dependent Kinase 2; D002166:Camptothecin