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Published ahead of print on June 7, 2007, doi:10.1165/rcmb.2007-0055OC

Am. J. Respir. Cell Mol. Biol., Volume 37, Number 4, October 2007, 457-466

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Submitted on February 21, 2007
Revised on June 7, 2007

Steroid and Oxygen Effects on eIF4F Complex, mTOR and ENaC Translation in Fetal Lung Epithelia

Gail Otulakowski1*, Wenming Duan2, Shephali Gandhi2, and Hugh O'Brodovich3

1 CIHR Group in Lung Development and Program in Physiology and Experimental Medicine, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada; Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada, 2 CIHR Group in Lung Development and Program in Physiology and Experimental Medicine, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada, 3 CIHR Group in Lung Development and Program in Physiology and Experimental Medicine, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada; Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada; Department of Physiology, University of Toronto, Toronto, Ontario, Canada

* To whom correspondence should be addressed. E-mail: gail.otulakowski{at}sickkids.ca.

Fetal distal lung epithelium (FDLE) must increase amiloride-sensitive epithelial Na+ channel (ENaC) activity during the perinatal period to increase Na+ transport and fluid clearance. Glucocorticosteroid (GC) levels increase, there is a 7-fold increase in pO2 at birth, and we have previously shown that dexamethasone (DEX)-induced {alpha}-ENaC mRNA is efficiently translated only under postnatal (21%) O2 (Otulakowski et al., AJRCMB 34:204-212, 2006). Translation of mRNAs with long GC-rich 5'UTRs, such as {alpha}-ENaC mRNA, are sensitive to the amount of eIF4F, the mRNA 5'-cap binding complex composed of eIF4E and eIF4G. We now show, by Western blotting and m7GTP-Sepharose pull-down experiments, that in FDLE cultured under 3% O2, DEX decreases formation of eIF4F and increases association of eIF4E with its inhibitor 4E-BP by changing 4E-BP phosphorylation. Conversely, FDLE cultured at 21% O2 expressed lower levels of 4E-BP and maintained eIF4E-eIF4G association independent of DEX. Phosphorylation of 4E-BP is regulated by the kinase mTOR. Under 3% O2, DEX decreased abundance of phosphorylated forms of the mTOR effectors, S6 kinase and ribosomal protein S6. Neither effect was associated with changes in REDD1, an upstream regulator of mTOR. When mTOR was inhibited (3nM rapamycin) there was reduced 4E-BP phosphorylation, fewer ribosomes on {alpha}-ENaC mRNA, and decreased amiloride-sensitive short-circuit current, but no change in ribosomal loading onto any of {beta}- or {gamma}-ENaC or cytokeratin 18 mRNAs. We speculate that at birth increased pO2 acts with GC through an mTOR-related pathway to increase {alpha}-ENaC protein synthesis thereby promoting lung fluid absorption.




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