Deletion of caveolin-1 protects hyperoxia-induced apoptosis via survivin-mediated pathways.
Hyperoxia-induced lung injury is an established model that mimics human acute respiratory distress syndrome. Cell death is a prominent feature in lungs following prolonged hyperoxia. Caveolae are omega-shaped invaginations of the plasma membrane. Caveolin-1 (cav-1), a 22-kDa transmembrane scaffolding protein, is the principal structural component of caveolae. We have recently shown that deletion of cav-1 (cav-1-/-) protected against hyperoxia-induced cell death and lung injury both in vitro and in vivo; however, the mechanisms remain unclear. Survivin, a member of the inhibitor of apoptosis protein family, inhibits apoptosis in tumor cells. Although emerging evidence suggests that survivin is involved in wound healing, especially in vascular injuries, its role in hyperoxia-induced lung injury has not been investigated. Our current data demonstrated that hyperoxia induced apoptosis via suppressing survivin expression. Deletion of cav-1 abolished this suppression and subsequently protected against hyperoxia-induced apoptosis. Using "gain" and "loss" of function assays, we determined that survivin protected lung cells from hyperoxia-induced apoptosis via the inhibition of apoptosis executor caspase-3. Overexpression of survivin by deletion of cav-1 was regulated by Egr-1. Egr-1 functioned as a negative regulator of survivin expression. Deletion of cav-1 upregulated survivin via decreased Egr-1 binding of the survivin promoter region. Together, this study illustrates the effect of hyperoxia on survivin expression and the role of survivin in hyperoxia-induced apoptosis. We also demonstrate that deletion of cav-1 protects hyperoxia-induced apoptosis via modulation of survivin expression.
Zhang
Meng
M
Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, MUH 628NW, 3459 5th Ave., Pittsburgh, PA 15213, USA.
Lin
Ling
L
Lee
Seon-Jin
SJ
Mo
Li
L
Cao
Jiaofei
J
Ifedigbo
Emeka
E
Jin
Yang
Y
D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D051242:Caveolin 1 / Q000172:deficiency* / Q000378:metabolism; D002478:Cells, Cultured; D019610:Cytoprotection; D015536:Down-Regulation / Q000235:genetics; D051766:Early Growth Response Protein 1 / Q000172:deficiency / Q000378:metabolism; D005347:Fibroblasts / Q000201:enzymology / Q000473:pathology; D017353:Gene Deletion; D006801:Humans; D018496:Hyperoxia / Q000378:metabolism / Q000473:pathology*; D051034:Inhibitor of Apoptosis Proteins; D008168:Lung / Q000473:pathology; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins; D015398:Signal Transduction; D000077022:Survivin; D014158:Transcription, Genetic
C107489:BIRC5 protein, human; C117749:Birc5 protein, mouse; D051242:Caveolin 1; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; D000077022:Survivin; D053148:Caspase 3