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1 Department of Environmental Medicine, The University of Rochester, Rochester, NY, USA
2 Department of Pediatrics, The University of Rochester, Rochester, NY, USA
3 Department of Pathology and Laboratory Medicine, The University of Rochester, Rochester, NY, USA
4 Department of Biochemistry and Biophysics, The University of Rochester, Rochester, NY, USA
5 Department of Radiation Oncology, The University of Rochester, School of Medicine and Dentistry, Oncology, NY, USA
* To whom correspondence should be addressed. E-mail: michael_oreilly{at}urmc.rochester.edu.
This study investigates molecular mechanisms underlying cell cycle arrest when cells are exposed to high levels of oxygen (hyperoxia). Hyperoxia has previously been shown to increase expression of the cell cycle regulators p53 and p21. In the current study, we found that p53-deficient human lung adenocarcinoma H1299 cells failed to induce p21 or growth arrest in G1 when exposed to 95% oxygen. Instead, cells arrested in S and G2. Stable expression of p53 restored induction of p21 and G1 arrest without affecting mRNA expression of the other Cip or INK4 G1 kinase inhibitors. To confirm the role of p21 in G1 arrest, H1299 cells with tetracycline-inducible expression of enhanced green fluorescent protein (EGFP), EGFP fused to p21 (EGFp21) or EGFP fused to p27 (EGFp27), a related cell cycle inhibitor, were created. The amino-terminus of p21 and p27 bind cyclin-dependent kinases (CDK) while the carboxy-terminus of p21 binds the sliding clamp proliferating cell nuclear antigen (PCNA). EGFp21 or EGFp27, but not EGFP by itself restored G1 arrest during hyperoxia. When separately over-expressed, the amino-terminal CDK and carboxy-terminal PCNA binding domains of p21 each prevented cells from exiting G1 during exposure. These findings demonstrate that exposure in vitro to hyperoxia exerts G1 arrest through p53-dependent induction of p21 that suppresses CDK and PCNA activity. Since PCNA also participates in DNA repair, these results raise the possibility that p21 also affects repair of oxidized DNA.
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