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Articles in PresS, published online ahead of print October 11, 2002
Am J Physiol Lung Cell Mol Physiol, 10.1152/ajplung.00299.2002
Submitted on August 30, 2002
Accepted on October 8, 2002
1 Department of Pediatrics, The University of Rochester, Rochester, NY, USA
2 Department of Pediatrics, The University of Rochester, Rochester, NY, USA; Department of Radiation Oncology, The University of Rochester, Rochester, NY, USA
3 Department of Radiation Oncology, The University of Rochester, Rochester, NY, USA
* To whom correspondence should be addressed. E-mail: michael_oreilly{at}urmc.rochester.edu.
Reactive oxygen species produced during hyperoxia damage DNA, inhibit proliferation in G1 through p53-dependent activation of p21 Cip1/WAF1/Sdi1 and kill cells. Because checkpoint activation protects cells from genotoxic stress, we investigated cell proliferation and survival of the murine type II epithelial cell line MLE15 during hyperoxia. These cells were chosen for study because they express simian large and small t antigens, which transform cells in part by disrupting the p53-dependent G1 checkpoint. Cell counts, 5-bromo-2'-deoxyuridine labeling and flow cytometry revealed that hyperoxia slowed cell cycle progression after one replication, resulting in a pronounced G2 arrest by 72 hours. Addition of caffeine, which inactivates the G2 checkpoint, diminished the percentage of hyperoxic cells in G2 and increased the percentage in subG1 and G1. Abrogation of the G2 checkpoint was associated with enhanced oxygen-induced DNA strand breaks and cell death. Caffeine did not affect DNA integrity or viability of cells exposed to room air. Similarly, caffeine abrogated the G2 checkpoint in hyperoxic A549 epithelial cells and enhanced oxygen-induced toxicity. These data indicate that hyperoxia rapidly inhibits proliferation after one cell cycle and that the G2 checkpoint is critical for limiting DNA damage and cell death.
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