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EDITORIAL FOCUS

The Cdk and PCNA domains on p21^Cip1 both function to inhibit G₁/S progression during hyperoxia

Departments of ¹Environmental Medicine, ²Pediatrics, ³Pathology and Laboratory Medicine, ⁴Biochemistry and Biophysics, and ⁵Radiation Oncology, School of Medicine and Dentistry, The University of Rochester, Rochester, New York 14642

Submitted 22 July 2003 ; accepted in final form 18 August 2003

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, we created 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. The amino terminus of p21 and p27 bind cyclin-dependent kinases (Cdk), whereas 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 overexpressed, 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. Because PCNA also participates in DNA repair, these results raise the possibility that p21 also affects repair of oxidized DNA.

cell cycle; DNA damage; proliferation; reactive oxygen species; proliferating cell nuclear antigen; cyclin-dependent kinase

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