Activation of pro-survival pathways during hyperoxic lung injury.
Reactive oxygen species (ROS) formed during aerobic respiration oxidize DNA, RNA, and proteins. Such damage can occur when lungs are exposed to hyperoxia or by the chronic exposure to oxygen over a lifetime. In order to prevent abnormal lung development or remodeling, it is essential that oxidative damage be recognized and repaired or terminally injured cells be efficiently removed and replaced.
Our studies have shown that hyperoxia sequentially activates hSMG-1, a phosphatidylinositol 3-kinase-like kinase involved in nonsense mediated mRNA decay, and the related kinase ATM, which recognizes DNA strand breaks. These kinases phosphorylate the tumor suppressor p53, an essential regulator of the cyclin-dependent kinase inhibitor p21 and pro-apoptotic protein PUMA. P21 in turn inhibits cell growth through binding cyclins and PCNA. It also protects against hyperoxia by maintaining expression of the anti-apoptotic proteins Bcl-XL and Mcl-1 that block Bax/Bak-dependent cell death.
Our laboratory is studying how hSMG-1 and ATM activate the p53/p21 pathway and how p21 selectively maintains expression of Bcl-XL and Mcl-1. By understanding how these pathways function during hyperoxia, we hope to ultimately minimize the harmful effects of oxygen supplementation in preterm infants.
Helt CE, Cliby WA, Keng PC, Bambara RA, and O'Reilly M A. Ataxia telangiectasia mutated (ATM) and ATM and Rad3-related protein exhibit selective target specificities in response to different forms of DNA damage. J Biol Chem 280: 1186-1192, 2005.
Staversky RJ, Vitiello PF, Gehen SC, Helt CE, Rahman A, Keng PC, and O'Reilly MA. p21(Cip1/Waf1/Sdi1) protects against hyperoxia by maintaining expression of Bcl-X(L). Free Radic Biol Med 41: 601-609, 2006.
Vitiello PF, Staversky RJ, Keng PC, and O'Reilly MA. PUMA inactivation protects against oxidative stress through p21/Bcl-XL inhibition of bax death. Free Radic Biol Med 44: 367-374, 2008.
Gehen SC, Staversky RJ, Bambara RA, Keng PC, and O'Reilly MA. hSMG-1 and ATM sequentially and independently regulate the G(1) checkpoint during oxidative stress. Oncogene 27: 4065-4074, 2008.