3 ALTERNATIVE PROMOTERS OF THE RAT GAMMA-GLUTAMYL-TRANSFERASE GENE ARE ACTIVE IN DEVELOPING LUNG AND ARE DIFFERENTIALLY REGULATED BY OXYGENAFTER BIRTH

The rat gamma-glutamyl transferase mRNA transcripts I, II, and III are derived from three alternative promoters, P-I, P-II, and P-III, In th e adult only mRNA III is expressed in the lung. We show that mRNA III gene expression is developmentally regulated in the fetal lung; it is first expressed late in gestation. In contrast to the adult lung, the fetal lung expresses mRNA I, II, and III, The switch from the fetal to the adult pattern of gamma GT mRNA expression begins within the first 24 h of birth and is complete by 10 d of age. gamma GT mRNA II disapp ears within 24 h, mRNA I disappears by 10 d leaving mRNA III as the so le transcript, Alveolar epithelial type 2 cells (AT2) isolated from th e adult lung express only mRNA III. When cultured in 21% O-2 mRNA III is maintained, but when cultured in 3% O-2 the fetal pattern of mRNA I , II and III expression is induced. When AT2 cells in hypoxia are expo sed to carbon monoxide, mRNA II is suppressed suggesting that a heme-b inding protein (responsive to oxygen) may suppress mRNA II expression and may be responsible for the decrease in lung mRNA II seen after bir th. A reporter gene under the control of DNA sequences from the gamma GT P-III promoter is activated in transient transfection studies in re sponse to hyperoxia, while a deletion construct retaining an antioxida nt responsive element is not, Oxygen appears to regulate each of the a lternative promoters of the gamma GT gene, such that P-II is rapidly r epressed by a heme-dependent mechanism, P-I is more gradually represse d by a nonheme mechanism and P-III is activated by a putative oxygen r esponse element. We hypothesize that similar oxygen-dependent mechanis ms regulate other genes in the developing lung at birth.