FOXO transcription factors enforce cell cycle checkpoints and promote survival of hematopoietic cells after DNA damage.
The PI3K/AKT signaling pathway contributes to cell cycle progression of cytokine-dependent hematopoietic cells under normal conditions, and it is absolutely required to override DNA damage-induced cell cycle arrest checkpoints in these cells. Phosphatidylinositol-3-kinase (PI3K)/AKT activity also correlates with Cdk2 activity in hematopoietic cells, suggesting that Cdk2 activation may be a relevant end point for this signaling pathway. However, mediators downstream of AKT in this pathway have not been defined. The forkhead transcription factor O (FOXO) family are negatively regulated by AKT-dependent phosphorylation and are known regulators of genes affecting cell cycle progression. We show that enhanced FOXO activity replicates the effect of PI3K inhibitors in enforcing G(1) and G(2) phase arrest after DNA damage. Conversely, knockdown of endogenous FOXO proteins increased Cdk2 activity and overrode DNA damage checkpoints in cells lacking PI3K activity. Moreover, loss of FOXO activity caused an increase in sensitivity to cisplatin-induced cell death, which was associated with failure to arrest cell cycle progression in the face of DNA damage caused by this chemotherapeutic agent. These cell cycle arrests were dependent on p27 expression when mediated by FOXO3a alone, but also involve p27-independent mechanisms when promoted by endogenous FOXO proteins. Together, these observations show that FOXO proteins enforce DNA damage-induced cell cycle arrest in hematopoietic cells. Inhibition of FOXO activity by cytokine-induced PI3K/AKT signaling is sufficient to override these DNA damage-induced cell cycle checkpoints, but may negatively impact hematopoietic cell viability.
Lei
Hong
H
Department of Pharmacology, The University of Iowa, Carver College of Medicine, Iowa City, IA 52242, USA.
Quelle
Frederick W
FW
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D016923:Cell Death / Q000187:drug effects / Q000528:radiation effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002945:Cisplatin / Q000494:pharmacology; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D004249:DNA Damage; D004351:Drug Resistance / Q000187:drug effects / Q000528:radiation effects; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005720:Gamma Rays; D055785:Gene Knockdown Techniques; D006413:Hematopoietic System / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D051379:Mice; D000081082:Phosphoinositide-3 Kinase Inhibitors
D051858:Forkhead Transcription Factors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D050760:Cyclin-Dependent Kinase Inhibitor p27; D002945:Cisplatin