Role of oxygen availability in CFTR expression and function.
The cystic fibrosis transmembrane conductance regulator (CFTR) serves a pivotal role in normal epithelial homeostasis; its absence leads to destruction of exocrine tissues, including those of the gastrointestinal tract and lung. Acute regulation of CFTR protein in response to environmental stimuli occurs at several levels (e.g., ion channel phosphorylation, ATP hydrolysis, apical membrane recycling). However, less information is available concerning the regulatory pathways that control levels of CFTR mRNA. In the present study, we investigated regulation of CFTR mRNA during oxygen restriction, examined effects of hypoxic signaling on chloride transport across cell monolayers, and related these findings to a possible role in the pathogenesis of chronic hypoxic lung disease. CFTR mRNA, protein, and function were robustly and reversibly altered in human cells in relation to hypoxia. In mice subjected to low oxygen in vivo, CFTR mRNA expression in airways, gastrointestinal tissues, and liver was repressed. CFTR mRNA expression was also diminished in pulmonary tissues taken from hypoxemic subjects at the time of lung transplantation. Environmental factors that induce hypoxic signaling regulate CFTR mRNA and epithelial Cl(-) transport in vitro and in vivo.
Guimbellot
Jennifer S
JS
Department of Genetics, Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL 35294-0005, USA.
Fortenberry
James A
JA
Siegal
Gene P
GP
Moore
Bryan
B
Wen
Hui
H
Venglarik
Charles
C
Chen
Yiu-Fai
YF
Oparil
Suzanne
S
Sorscher
Eric J
EJ
Hong
Jeong S
JS
D000818:Animals; D015687:Cell Hypoxia; D002460:Cell Line; D017077:Culture Media, Conditioned; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics* / Q000378:metabolism*; D015536:Down-Regulation; D005786:Gene Expression Regulation / Q000235:genetics*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D010100:Oxygen / Q000378:metabolism*
D017077:Culture Media, Conditioned; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D010100:Oxygen