Phosphoinositide 3-kinase signaling overrides a G2 phase arrest checkpoint and promotes aberrant cell cycling and death of hematopoietic cells after DNA damage

Dipali Nimbalkar; Frederick W Quelle

doi:10.4161/cc.7.18.6675

Back

Phosphoinositide 3-kinase signaling overrides a G2 phase arrest checkpoint and promotes aberrant cell cycling and death of hematopoietic cells after DNA damage

Journal article

Open access

Peer reviewed

Phosphoinositide 3-kinase signaling overrides a G2 phase arrest checkpoint and promotes aberrant cell cycling and death of hematopoietic cells after DNA damage

Dipali Nimbalkar and Frederick W Quelle

Cell cycle (Georgetown, Tex.), Vol.7(18), pp.2877-2885

09/15/2008

DOI: 10.4161/cc.7.18.6675

PMID: 18769155

Files and links (1)

url

https://doi.org/10.4161/cc.7.18.6675View

Published (Version of record) Open Access

Abstract

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.

Cell Line

Gamma Rays

Cell Death - radiation effects

G2 Phase - radiation effects

Humans

Cell Cycle Proteins - metabolism

Phosphatidylinositol 3-Kinases - metabolism

Hematopoietic System - cytology

Metaphase - radiation effects

Animals

Hematopoietic System - radiation effects

Mice

DNA Damage

Signal Transduction - radiation effects

Details

Title: Subtitle: Phosphoinositide 3-kinase signaling overrides a G2 phase arrest checkpoint and promotes aberrant cell cycling and death of hematopoietic cells after DNA damage
Creators: Dipali Nimbalkar - Department of Pharmacology, The University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA
Frederick W Quelle
Resource Type: Journal article
Publication Details: Cell cycle (Georgetown, Tex.), Vol.7(18), pp.2877-2885
DOI: 10.4161/cc.7.18.6675
PMID: 18769155
NLM abbreviation: Cell Cycle
ISSN: 1538-4101
eISSN: 1551-4005
Publisher: United States
Grant note: R01 CA79889 / NCI NIH HHS
Language: English
Date published: 09/15/2008
Academic Unit: Neuroscience and Pharmacology; Internal Medicine
Record Identifier: 9984040200602771

Metrics

13 Record Views

11 Times Cited - Web of Science