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J. Biol. Chem., Vol. 278, Issue 38, 36099-36106, September 19, 2003

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Hyperoxia Induces Macrophage Cell Cycle Arrest by Adhesion-dependent Induction of p21^Cip1 and Activation of the Retinoblastoma Protein^*

Toru Nyunoya , Linda S. Powers, Timur O. Yarovinsky, Noah S. Butler, Martha M. Monick and Gary W. Hunninghake

From the Division of Pulmonary, Critical Care, and Occupational Medicine, University of Iowa Roy J. and Lucille A. Carver College of Medicine and Veterans Administration Medical Center, Iowa City, Iowa 52242

Hyperoxia induces growth arrest, apoptosis, necrosis, and morphological changes (spreading and adhesion) in various types of cells. The mechanism of hyperoxia-induced cell growth arrest has not been well elucidated, especially in macrophages. One possible mechanism is a role of cell adhesion in hyperoxia-induced cell cycle arrest. To evaluate this finding, macrophages were cultured in normoxia (21% O₂) or hyperoxia (95% O₂) in adhesion or low adhesion conditions. Incubation of macrophages in hyperoxia induced cell cycle arrest. The hyperoxia-induced cell cycle arrest was prevented by low adhesion conditions. To evaluate pathways potentially involved in hyperoxia-induced growth arrest, we measured extracellular regulated kinase and retinoblastoma protein activation and p21^Cip1 and p53 accumulation. Hyperoxia strongly induced activation of extracellular regulated kinase and retinoblastoma protein as well as up-regulation of p21^Cip1. These effects of hyperoxia were attenuated under low adhesion conditions, suggesting a role for integrin-dependent signaling. The induction of p21^Cip1 and activation of retinoblastoma protein occurred via a p53-independent mechanism. These results suggest that adhesion-dependent pathways are required for hyperoxia-induced cell cycle arrest in macrophages.

Received for publication, April 26, 2003 , and in revised form, June 23, 2003.

^* This work was supported by a Veterans Administration merit review grant, National Institutes of Health Grants HL-60316 and ES-09607, Environmental Protection Agency Grant R826711 (to G. W. H.), and National Center for Research Resources, National Institutes of Health Grant RR00059 from the General Clinical Research Centers Program. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Division of Pulmonary, Critical Care, and Occupational Medicine, 100 Ekstein Medical Research Bldg., Iowa City, IA 52242. Tel.: 319-335-7590; Fax: 319-335-6530; E-mail:toru-nyunoya{at}uiowa.edu.

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