title: Glucocorticoid-mediated repression of REDD1 mRNA expression in rat fetal distal lung epithelial cells.
abstract: REDD1 (Regulated in Development and DNA Damage-1) is a stress-response gene that represses mammalian target of rapamycin (mTOR) thus decreasing protein synthesis. In contrast to studies using cell lines and adult alveolar type II (ATII) cells, we find that REDD1 mRNA levels did not increase in rat fetal distal lung epithelia (FDLE) or fetal lung fibroblasts grown in primary cultures and then exposed to 3% O2. REDD1 mRNA expression was repressed by dexamethasone (DEX) in FDLE and ATII, but induced by DEX in fibroblasts. Lung epithelial cell lines, A549 and MLE-15, showed increases in REDD1 mRNA in response to hypoxia and DEX. The effect of DEX on REDD1 mRNA and protein in FDLE and fibroblasts was dose- and time-dependent. Inhibitor studies support repression of REDD1 mRNA by DEX in FDLE was mediated via glucocorticoid receptor and not by nongenomic effects of glucocorticoids via MAPK pathways. The half-life of REDD1 mRNA was shorter in DEX-exposed FDLE compared with hormone-free media suggesting that DEX reduced REDD1 mRNA stability in FDLE. These studies indicate that REDD1 expression in response to hypoxia and DEX is cell-type specific and that physiologically appropriate levels of PO2 should be used when investigating fetal lung development.
authors.affiliation: CIHR Group in Lung Development, Program in Physiology and Experimental Medicine, Hospital for Sick Children Research Institute, Toronto, Ontario, M5G 1X8, Canada. gail.otulakowski@sickkids.ca
authors.forename: Gail
authors.initials: G
authors.lastname: Otulakowski
authors.forename: Wenming
authors.initials: W
authors.lastname: Duan
authors.forename: Aparna
authors.initials: A
authors.lastname: Sarangapani
authors.forename: Shephali
authors.initials: S
authors.lastname: Gandhi
authors.forename: Hugh
authors.initials: H
authors.lastname: O'Brodovich
mesh_terms: D000367:Age Factors; D000818:Animals; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005865:Gestational Age; D005938:Glucocorticoids / Q000494:pharmacology*; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D008168:Lung / Q000187:drug effects* / Q000196:embryology / Q000378:metabolism; D008297:Male; D015735:Mifepristone / Q000494:pharmacology; D010100:Oxygen / Q000378:metabolism*; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics*; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C469991:DDIT4 protein, human; C000632146:Ddit4 protein, rat; D005938:Glucocorticoids; D006727:Hormone Antagonists; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D012097:Repressor Proteins; D014157:Transcription Factors; D015735:Mifepristone; D003907:Dexamethasone; D048051:p38 Mitogen-Activated Protein Kinases; D010100:Oxygen