Phosphoinositide 3-kinase signaling overrides a G2 phase arrest checkpoint and promotes aberrant cell cycling and death of hematopoietic cells after DNA damage.
DNA damage activates arrest checkpoints to halt cell cycle progression in G(1) and G(2) phases. These checkpoints can be overridden in hematopoietic cells by cytokines, such as erythropoietin, through the activation of a phosphoinositide 3-kinase (PI3K) signaling pathway. Here, we show that PI3K activity specifically overrides delayed mechanisms effecting permanent G(1) and G(2) phase arrests, but does not affect transient checkpoints arresting cells up to 10 hours after gamma-irradiation. Assessing the status of cell cycle regulators in hematopoietic cells arrested after gamma-irradiation, we show that Cdk2 activity is completely inhibited in both G(1) and G(2) arrested cells. Despite the absence of Cdk2 activity, cells arrested in G(2) phase did retain detectable levels of Cdk1 activity in the absence of PI3K signaling. However, reactivation of PI3K promoted robust increases in both Cdk1 and Cdk2 activity in G(2)-arrested cells. Reactivation of Cdks was accompanied by a resumption of cell cycling, but with strikingly different effectiveness in G(1) and G(2) phase arrested cells. Specifically, G(1)-arrested cells resumed normal cell cycle progression with little loss in viability when PI3K was activated after gamma-irradiation. Conversely, PI3K activation in G(2)-arrested cells promoted endoreduplication and death of the entire population. These observations show that cytokine-induced PI3K signaling pathways promote Cdk activation and override permanent cell cycle arrest checkpoints in hematopoietic cells. While this activity can rescue irradiated cells from permanent G(1) phase arrest, it results in aberrant cell cycling and death when activated in hematopoietic cells arrested at the G(2) phase DNA damage checkpoint.
Nimbalkar
Dipali
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Department of Pharmacology, The University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.
Quelle
Frederick W
FW