Am. J. Respir. Cell Mol. Biol., Volume 18, Number 2, February, 1998 179-187

Induction of p21^WAF/CIP1 during Hyperoxia

Sharon A. McGrath

Department of Pediatrics, Eudowood Division of Pediatric Respiratory Sciences, Johns Hopkins Medical Institutions, Baltimore, Maryland

p21^WAF/CIP1 is an important regulator of cell cycle progression (). When induced, p21^WAF/CIP1 protein inhibits cell cycle progression at the G₁/S interface, resulting in growth arrest of the cell. To determine if p21^WAF/CIP1 is involved in growth arrest and lung injury during hyperoxia, several cell lines were exposed to high levels of hyperoxia. p21^WAF/CIP1 was found to be induced by 72 h in all three cell lines. Next, using an in vivo model, p21^WAF/CIP1 was found to be induced at both the mRNA and protein level in neonatal murine lung born and maintained in hyperoxia. Localization of p21^WAF/CIP1 was found in the peripheral airway cells. Hyperoxia-induced p21^WAF/CIP1 expression was then shown to be mediated through the p53 pathway, using adult p53 mutant mice. These studies demonstrated that p21^WAF/CIP1 is induced both in cells grown in culture and in neonatal and adult lung exposed to high levels of hyperoxia. Localization of p21^WAF/CIP1 expression to the peripheral airway cells suggests that p21^WAF/CIP1 may act to inhibit growth of alveoli in neonatal lung and delay repopulation of alveolar cells during hyperoxic administration.

This article has been cited by other articles:

				S. McGrath-Morrow, T. Lauer, M. Yee, E. Neptune, M. Podowski, R. K. Thimmulappa, M. O'Reilly, and S. Biswal Nrf2 increases survival and attenuates alveolar growth inhibition in neonatal mice exposed to hyperoxia Am J Physiol Lung Cell Mol Physiol, April 1, 2009; 296(4): L565 - L573. [Abstract] [Full Text] [PDF]

				Q. Mao, S. Gundavarapu, C. Patel, A. Tsai, F. I. Luks, and M. E. De Paepe The Fas System Confers Protection against Alveolar Disruption in Hyperoxia-Exposed Newborn Mice Am. J. Respir. Cell Mol. Biol., December 1, 2008; 39(6): 717 - 729. [Abstract] [Full Text] [PDF]

				A. Chambellan, P. J. Cruickshank, P. McKenzie, S. B. Cannady, K. Szabo, S. A. A. Comhair, and S. C. Erzurum Gene Expression Profile of Human Airway Epithelium Induced by Hyperoxia In Vivo Am. J. Respir. Cell Mol. Biol., October 1, 2006; 35(4): 424 - 435. [Abstract] [Full Text] [PDF]

				J. Lee, R. Reddy, L. Barsky, K. Weinberg, and B. Driscoll Contribution of proliferation and DNA damage repair to alveolar epithelial type 2 cell recovery from hyperoxia Am J Physiol Lung Cell Mol Physiol, April 1, 2006; 290(4): L685 - L694. [Abstract] [Full Text] [PDF]

				J. S. Shenberger, J. L. Myers, S. G. Zimmer, R. J. Powell, and A. Barchowsky Hyperoxia alters the expression and phosphorylation of multiple factors regulating translation initiation Am J Physiol Lung Cell Mol Physiol, March 1, 2005; 288(3): L442 - L449. [Abstract] [Full Text] [PDF]

				S. V. Truong, M. M. Monick, T. O. Yarovinsky, L. S. Powers, T. Nyunoya, and G. W. Hunninghake Extracellular Signal-Regulated Kinase Activation Delays Hyperoxia-Induced Epithelial Cell Death in Conditions of Akt Downregulation Am. J. Respir. Cell Mol. Biol., December 1, 2004; 31(6): 611 - 618. [Abstract] [Full Text] [PDF]

				S. A. McGrath-Morrow, C. Cho, S. Soutiere, W. Mitzner, and R. Tuder The Effect of Neonatal Hyperoxia on the Lung of p21Waf1/Cip1/Sdi1-Deficient Mice Am. J. Respir. Cell Mol. Biol., May 1, 2004; 30(5): 635 - 640. [Abstract] [Full Text] [PDF]

				C. E. Helt, R. J. Staversky, Y.-J. Lee, R. A. Bambara, P. C. Keng, and M. A. O'Reilly The Cdk and PCNA domains on p21Cip1 both function to inhibit G1/S progression during hyperoxia Am J Physiol Lung Cell Mol Physiol, March 1, 2004; 286(3): L506 - L513. [Abstract] [Full Text] [PDF]

				M. A. O'Reilly, R. H. Watkins, R. J. Staversky, and W. M. Maniscalco Induced p21Cip1 in premature baboons with CLD: implications for alveolar hypoplasia Am J Physiol Lung Cell Mol Physiol, October 1, 2003; 285(4): L964 - L971. [Abstract] [Full Text] [PDF]

				T. Nyunoya, L. S. Powers, T. O. Yarovinsky, N. S. Butler, M. M. Monick, and G. W. Hunninghake Hyperoxia Induces Macrophage Cell Cycle Arrest by Adhesion-dependent Induction of p21Cip1 and Activation of the Retinoblastoma Protein J. Biol. Chem., September 19, 2003; 278(38): 36099 - 36106. [Abstract] [Full Text] [PDF]

				X. Wang, S. W. Ryter, C. Dai, Z.-L. Tang, S. C. Watkins, X.-M. Yin, R. Song, and A. M. K. Choi Necrotic Cell Death in Response to Oxidant Stress Involves the Activation of the Apoptogenic Caspase-8/Bid Pathway J. Biol. Chem., August 1, 2003; 278(31): 29184 - 29191. [Abstract] [Full Text] [PDF]

				S. Perkowski, J. Sun, S. Singhal, J. Santiago, G. D. Leikauf, and S. M. Albelda Gene Expression Profiling of the Early Pulmonary Response to Hyperoxia in Mice Am. J. Respir. Cell Mol. Biol., June 1, 2003; 28(6): 682 - 696. [Abstract] [Full Text] [PDF]

				R. J. Staversky, R. H. Watkins, T. W. Wright, E. Hernady, M. B. LoMonaco, C. T. D'Angio, J. P. Williams, W. M. Maniscalco, and M. A. O'Reilly Normal Remodeling of the Oxygen-Injured Lung Requires the Cyclin-Dependent Kinase Inhibitor p21Cip1/WAF1/Sdi1 Am. J. Pathol., October 1, 2002; 161(4): 1383 - 1393. [Abstract] [Full Text] [PDF]

				S. A. McGrath-Morrow and J. Stahl Apoptosis in Neonatal Murine Lung Exposed to Hyperoxia Am. J. Respir. Cell Mol. Biol., August 1, 2001; 25(2): 150 - 155. [Abstract] [Full Text] [PDF]

				M. A. O'Reilly DNA damage and cell cycle checkpoints in hyperoxic lung injury: braking to facilitate repair Am J Physiol Lung Cell Mol Physiol, August 1, 2001; 281(2): L291 - L305. [Abstract] [Full Text] [PDF]

				M. A. O'Reilly, R. J. Staversky, R. H. Watkins, C. K. Reed, K. L. de Mesy Jensen, J. N. Finkelstein, and P. C. Keng The Cyclin-Dependent Kinase Inhibitor p21 Protects the Lung from Oxidative Stress Am. J. Respir. Cell Mol. Biol., June 1, 2001; 24(6): 703 - 710. [Abstract] [Full Text] [PDF]

				R. C. Rancourt, P. C. Keng, C. E. Helt, and M. A. O'Reilly The role of p21CIP1/WAF1 in growth of epithelial cells exposed to hyperoxia Am J Physiol Lung Cell Mol Physiol, April 1, 2001; 280(4): L617 - L626. [Abstract] [Full Text] [PDF]

				S. L. Green, R. A. Freiberg, and A. J. Giaccia p21Cip1 and p27Kip1 Regulate Cell Cycle Reentry after Hypoxic Stress but Are Not Necessary for Hypoxia-Induced Arrest Mol. Cell. Biol., February 15, 2001; 21(4): 1196 - 1206. [Abstract] [Full Text]

				S. A. McGrath-Morrow and J. L. Stahl G1 Phase Growth Arrest and Induction of p21Waf1/Cip1/Sdi1 in IB3-1 Cells Treated with 4-Sodium Phenylbutyrate J. Pharmacol. Exp. Ther., September 1, 2000; 294(3): 941 - 947. [Abstract] [Full Text]

				M. A. O'Reilly, R. J. Staversky, R. H. Watkins, W. M. Maniscalco, and P. C. Keng p53-independent induction of GADD45 and GADD153 in mouse lungs exposed to hyperoxia Am J Physiol Lung Cell Mol Physiol, March 1, 2000; 278(3): L552 - L559. [Abstract] [Full Text] [PDF]

				J. S. Shenberger and P. S. Dixon Oxygen Induces S-Phase Growth Arrest and Increases p53 and p21WAF1/CIP1 Expression in Human Bronchial Smooth-Muscle Cells Am. J. Respir. Cell Mol. Biol., September 1, 1999; 21(3): 395 - 402. [Abstract] [Full Text]

				D. W Kamp and S. A Weitzman The molecular basis of asbestos induced lung injury Thorax, July 1, 1999; 54(7): 638 - 652. [Full Text]

				C. Barazzone, Y. R. Donati, A. F. Rochat, C. Vesin, C.-D. Kan, J. C. Pache, and P. F. Piguet Keratinocyte Growth Factor Protects Alveolar Epithelium and Endothelium from Oxygen-Induced Injury in Mice Am. J. Pathol., May 1, 1999; 154(5): 1479 - 1487. [Abstract] [Full Text] [PDF]

				L. Charafeddine, C. T. D'Angio, J. L. Richards, B. R. Stripp, J. N. Finkelstein, C. C. Orlowski, M. B. LoMonaco, A. Paxhia, and R. M. Ryan Hyperoxia increases keratinocyte growth factor mRNA expression in neonatal rabbit lung Am J Physiol Lung Cell Mol Physiol, January 1, 1999; 276(1): L105 - L113. [Abstract] [Full Text] [PDF]