Logo image
Back
FOXO transcription factors enforce cell cycle checkpoints and promote survival of hematopoietic cells after DNA damage
Journal article   Peer reviewed

FOXO transcription factors enforce cell cycle checkpoints and promote survival of hematopoietic cells after DNA damage

Hong Lei and Frederick W Quelle
Molecular cancer research, Vol.7(8), pp.1294-1303
08/2009
DOI: 10.1158/1541-7786.MCR-08-0531
PMID: 19671690

View Online

Abstract

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.
 Cell Line Cell Survival - drug effects Gamma Rays Cell Death - radiation effects Cell Cycle - radiation effects Hematopoietic System - drug effects Drug Resistance - drug effects Cisplatin - pharmacology Phosphatidylinositol 3-Kinases - antagonists & inhibitors Cell Survival - radiation effects Gene Knockdown Techniques Hematopoietic System - cytology Cyclin-Dependent Kinase Inhibitor p27 - metabolism Animals Hematopoietic System - metabolism Forkhead Transcription Factors - metabolism Drug Resistance - radiation effects Hematopoietic System - radiation effects Cell Proliferation - drug effects Mice Cell Death - drug effects DNA Damage Cell Cycle - drug effects Cell Proliferation - radiation effects

Details

Metrics

15 Record Views
38 Times Cited - Web of Science
Logo image