p53-independent induction of GADD45 and GADD153 in mouse lungs exposed to hyperoxia.
Previous studies have shown that lungs of adult mice exposed to >95% oxygen have increased terminal deoxyribonucleotidyltransferase dUTP nick end-label staining and accumulate p53, the expression of which increases in cells exposed to DNA-damaging agents. The present study was designed to determine whether hyperoxia also increased expression of the growth arrest and DNA damage (GADD) gene 45 and GADD153, which are induced by genotoxic stress through p53-dependent and -independent pathways. GADD proteins have been shown to inhibit proliferation and stimulate DNA repair and/or apoptosis. GADD45 and GADD153 mRNAs were not detected in lungs exposed to room air but were detected after 48 and 72 h of exposure to hyperoxia. In situ hybridization and immunohistochemistry revealed that hyperoxia increased GADD45 and GADD153 expression in the bronchiolar epithelium and GADD45 expression predominantly in alveolar cells that were morphologically consistent with type II cells. Hyperoxia also increased GADD expression in p53-deficient mice. Terminal deoxyribonucleotidyltransferase dUTP nick end-label staining of lung cells from p53 wild-type and p53-null mice exposed to hyperoxia for 48 h revealed that hyperoxia-induced DNA fragmentation was not modified by p53 deficiency. These studies are consistent with the hypothesis that hyperoxia-induced DNA fragmentation is associated with the expression of GADD genes that may participate in DNA repair and/or apoptosis.
O'Reilly
M A
MA
Division of Neonatology, Department of Pediatrics, and Department of Radiation Oncology, School of Medicine and Dentistry, University of Rochester, Rochester, New York 14642, USA. michael_oreilly@urmc.rochester.edu
Staversky
R J
RJ
Watkins
R H
RH
Maniscalco
W M
WM
Keng
P C
PC
D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins; D053938:DNA Fragmentation; D004268:DNA-Binding Proteins / Q000235:genetics*; D005786:Gene Expression Regulation; D018496:Hyperoxia / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins; D008168:Lung / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D000097642:GADD45 Proteins
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D012333:RNA, Messenger; D051742:Transcription Factor CHOP; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D000097642:GADD45 Proteins; C497250:Ddit3 protein, mouse