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Oxygen and dexamethasone modulate αENaC translation in fetal lung epithelia via availability of eIF4F
Author(s) -
Otulakowski Gail,
Duan Wenming,
Rafii Bijan,
O'Brodovich Hugh
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.lb29
Subject(s) - epithelial sodium channel , eif4g , eif4e , messenger rna , polysome , biology , medicine , endocrinology , microbiology and biotechnology , chemistry , translation (biology) , biochemistry , gene , rna , organic chemistry , sodium , ribosome
At birth, fetal distal lung epithelia (FDLE) must rapidly upregulate Na + transport, the rate limiting step of which is the amiloride‐sensitive epithelial Na + channel (ENaC). Although glucocorticoids (GC) mature the fetal lung it is unknown how GC interact with pO 2 at birth to induce lung fluid absorption. We found that dexamethasone (DEX)‐induced αENaC mRNA was efficiently translated into protein in primary cultures of FDLE only under postnatal (21%) O 2 (Otulakowski et al., AJRCMB;in press). Sucrose density gradient analyses of polysomes showed changes in αENaC mRNA distribution consistent with specific modulation of αENaC translation initiation; ie. DEX treatment of cells under fetal (3%) O 2 decreased association of αENaC mRNA with large polysomes, while shifting DEX‐treated cells to 21% O 2 restored association with large polysomes. αENaC mRNA possesses a long 5′UTR with a high GC content near the 5′‐cap, typical of mRNAs sensitive to limiting availability of eIF4F, the mRNA 5′‐cap binding complex composed of eIF4E and eIF4G. Western blots and m 7 GTP‐Sepharose pull‐down experiments showed DEX decreased formation of eIF4F and increased association of eIF4E with its inhibitor 4E‐BP in FDLE cultured at 3% O 2 , mediated by changes in 4E‐BP phosphorylation. Conversely, FDLE cultured at 21% O 2 expressed lower levels of 4E‐BP and maintained eIF4E‐eIF4G association in the presence of DEX. This suggests that the 7‐fold increase in pO 2 acts synergistically with GC to prepare the newborn lung to actively absorb fetal lung liquid. Supported by CIHR.