Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1996 Apr 1;97(7):1774–1779. doi: 10.1172/JCI118605

Three alternative promoters of the rat gamma-glutamyl transferase gene are active in developing lung and are differentially regulated by oxygen after birth.

M Joyce-Brady 1, S M Oakes 1, D Wuthrich 1, Y Laperche 1
PMCID: PMC507243  PMID: 8601644

Abstract

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 the 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 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 gammaGT mRNA expression begins within the first 24 h of birth and is complete by 10 d of age. gammaGT mRNA II disappears within 24 h, mRNA I disappears by 10 d leaving mRNA III as the sole transcript. Alveolar epithelial type 2 cells (AT2) isolated from the adult lung express only mRNA III. When cultured in 21% O2 mRNA III is maintained, but when cultured in 3% O2 the fetal pattern of mRNA I, II and III expression is induced. When AT2 cells in hypoxia are exposed to carbon monoxide, mRNA II is suppressed suggesting that a heme-binding protein (responsive to oxygen) may suppress mRNA II expression and may be responsible for the decrease in lung mRNA II seen after birth. A reporter gene under the control of DNA sequences from the gammaGT P(III) promoter is activated in transient transfection studies in response to hyperoxia, while a deletion construct retaining an antioxidant responsive element is not. Oxygen appears to regulate each of the alternative promoters of the gammaGT gene, such that P(II) is rapidly repressed by a heme-dependent mechanism, P(I), is more gradually repressed by a nonheme mechanism and P(III) is activated by a putative oxygen response element. We hypothesize that similar oxygen-dependent mechanisms regulate other genes in the developing lung at birth.

Full Text

The Full Text of this article is available as a PDF (253.3 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Brouillet A., Darbouy M., Okamoto T., Chobert M. N., Lahuna O., Garlatti M., Goodspeed D., Laperche Y. Functional characterization of the rat gamma-glutamyl transpeptidase promoter that is expressed and regulated in the liver and hepatoma cells. J Biol Chem. 1994 May 27;269(21):14878–14884. [PubMed] [Google Scholar]
  2. Cantin A. M., North S. L., Hubbard R. C., Crystal R. G. Normal alveolar epithelial lining fluid contains high levels of glutathione. J Appl Physiol (1985) 1987 Jul;63(1):152–157. doi: 10.1152/jappl.1987.63.1.152. [DOI] [PubMed] [Google Scholar]
  3. Clement A., Steele M. P., Brody J. S., Riedel N. SV40T-immortalized lung alveolar epithelial cells display post-transcriptional regulation of proliferation-related genes. Exp Cell Res. 1991 Oct;196(2):198–205. doi: 10.1016/0014-4827(91)90251-o. [DOI] [PubMed] [Google Scholar]
  4. Cowan D. B., Weisel R. D., Williams W. G., Mickle D. A. Identification of oxygen responsive elements in the 5'-flanking region of the human glutathione peroxidase gene. J Biol Chem. 1993 Dec 25;268(36):26904–26910. [PubMed] [Google Scholar]
  5. Darbouy M., Chobert M. N., Lahuna O., Okamoto T., Bonvalet J. P., Farman N., Laperche Y. Tissue-specific expression of multiple gamma-glutamyl transpeptidase mRNAs in rat epithelia. Am J Physiol. 1991 Dec;261(6 Pt 1):C1130–C1137. doi: 10.1152/ajpcell.1991.261.6.C1130. [DOI] [PubMed] [Google Scholar]
  6. Diederich M., Wellman M., Visvikis A., Puga A., Siest G. The 5' untranslated region of the human gamma-glutamyl transferase mRNA contains a tissue-specific active translational enhancer. FEBS Lett. 1993 Oct 11;332(1-2):88–92. doi: 10.1016/0014-5793(93)80490-l. [DOI] [PubMed] [Google Scholar]
  7. Forkert P. G., Moussa M. Histochemical localization of glutathione in fixed tissues. Histochem J. 1989 Nov;21(11):634–637. doi: 10.1007/BF01002482. [DOI] [PubMed] [Google Scholar]
  8. Goldberg M. A., Dunning S. P., Bunn H. F. Regulation of the erythropoietin gene: evidence that the oxygen sensor is a heme protein. Science. 1988 Dec 9;242(4884):1412–1415. doi: 10.1126/science.2849206. [DOI] [PubMed] [Google Scholar]
  9. Graven K. K., Troxler R. F., Kornfeld H., Panchenko M. V., Farber H. W. Regulation of endothelial cell glyceraldehyde-3-phosphate dehydrogenase expression by hypoxia. J Biol Chem. 1994 Sep 30;269(39):24446–24453. [PubMed] [Google Scholar]
  10. Halliwell B. Oxidants and human disease: some new concepts. FASEB J. 1987 Nov;1(5):358–364. [PubMed] [Google Scholar]
  11. Hwang C., Sinskey A. J., Lodish H. F. Oxidized redox state of glutathione in the endoplasmic reticulum. Science. 1992 Sep 11;257(5076):1496–1502. doi: 10.1126/science.1523409. [DOI] [PubMed] [Google Scholar]
  12. Joyce-Brady M. F., Brody J. S. Ontogeny of pulmonary alveolar epithelial markers of differentiation. Dev Biol. 1990 Feb;137(2):331–348. doi: 10.1016/0012-1606(90)90258-k. [DOI] [PubMed] [Google Scholar]
  13. Joyce-Brady M., Rubins J. B., Panchenko M. P., Bernardo J., Steele M. P., Kolm L., Simons E. R., Dickey B. F. Mechanisms of mastoparan-stimulated surfactant secretion from isolated pulmonary alveolar type 2 cells. J Biol Chem. 1991 Apr 15;266(11):6859–6865. [PubMed] [Google Scholar]
  14. Joyce-Brady M., Takahashi Y., Oakes S. M., Rishi A. K., Levine R. A., Kinlough C. L., Hughey R. P. Synthesis and release of amphipathic gamma-glutamyl transferase by the pulmonary alveolar type 2 cell. Its redistribution throughout the gas exchange portion of the lung indicates a new role for surfactant. J Biol Chem. 1994 May 13;269(19):14219–14226. [PubMed] [Google Scholar]
  15. Laperche Y., Bulle F., Aissani T., Chobert M. N., Aggerbeck M., Hanoune J., Guellaën G. Molecular cloning and nucleotide sequence of rat kidney gamma-glutamyl transpeptidase cDNA. Proc Natl Acad Sci U S A. 1986 Feb;83(4):937–941. doi: 10.1073/pnas.83.4.937. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Maitre B., Clement A., Williams M. C., Brody J. S. Expression of insulin-like growth factor receptors 1 and 2 in the developing lung and their relation to epithelial cell differentiation. Am J Respir Cell Mol Biol. 1995 Sep;13(3):262–270. doi: 10.1165/ajrcmb.13.3.7654382. [DOI] [PubMed] [Google Scholar]
  17. Meister A. Glutathione deficiency produced by inhibition of its synthesis, and its reversal; applications in research and therapy. Pharmacol Ther. 1991;51(2):155–194. doi: 10.1016/0163-7258(91)90076-x. [DOI] [PubMed] [Google Scholar]
  18. Meister A. Methods for the selective modification of glutathione metabolism and study of glutathione transport. Methods Enzymol. 1985;113:571–585. doi: 10.1016/s0076-6879(85)13077-6. [DOI] [PubMed] [Google Scholar]
  19. Nudel U., Zakut R., Shani M., Neuman S., Levy Z., Yaffe D. The nucleotide sequence of the rat cytoplasmic beta-actin gene. Nucleic Acids Res. 1983 Mar 25;11(6):1759–1771. doi: 10.1093/nar/11.6.1759. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Okamoto T., Darbouy M., Brouillet A., Lahuna O., Chobert M. N., Laperche Y. Expression of the rat gamma-glutamyl transpeptidase gene from a specific promoter in the small intestine and in hepatoma cells. Biochemistry. 1994 Sep 27;33(38):11536–11543. doi: 10.1021/bi00204a016. [DOI] [PubMed] [Google Scholar]
  21. Pahl H. L., Baeuerle P. A. Oxygen and the control of gene expression. Bioessays. 1994 Jul;16(7):497–502. doi: 10.1002/bies.950160709. [DOI] [PubMed] [Google Scholar]
  22. Paine R., Ben-Ze'ev A., Farmer S. R., Brody J. S. The pattern of cytokeratin synthesis is a marker of type 2 cell differentiation in adult and maturing fetal lung alveolar cells. Dev Biol. 1988 Oct;129(2):505–515. doi: 10.1016/0012-1606(88)90396-x. [DOI] [PubMed] [Google Scholar]
  23. Pang J. H., Hung R. Y., Wu C. J., Fang Y. Y., Chau L. Y. Functional characterization of the promoter region of the platelet-activating factor receptor gene. Identification of an initiator element essential for gene expression in myeloid cells. J Biol Chem. 1995 Jun 9;270(23):14123–14129. doi: 10.1074/jbc.270.23.14123. [DOI] [PubMed] [Google Scholar]
  24. Rushmore T. H., Morton M. R., Pickett C. B. The antioxidant responsive element. Activation by oxidative stress and identification of the DNA consensus sequence required for functional activity. J Biol Chem. 1991 Jun 25;266(18):11632–11639. [PubMed] [Google Scholar]
  25. Schibler U., Sierra F. Alternative promoters in developmental gene expression. Annu Rev Genet. 1987;21:237–257. doi: 10.1146/annurev.ge.21.120187.001321. [DOI] [PubMed] [Google Scholar]
  26. Schmidt K. N., Amstad P., Cerutti P., Baeuerle P. A. The roles of hydrogen peroxide and superoxide as messengers in the activation of transcription factor NF-kappa B. Chem Biol. 1995 Jan;2(1):13–22. doi: 10.1016/1074-5521(95)90076-4. [DOI] [PubMed] [Google Scholar]
  27. Smale S. T., Baltimore D. The "initiator" as a transcription control element. Cell. 1989 Apr 7;57(1):103–113. doi: 10.1016/0092-8674(89)90176-1. [DOI] [PubMed] [Google Scholar]
  28. Wang G. L., Semenza G. L. Characterization of hypoxia-inducible factor 1 and regulation of DNA binding activity by hypoxia. J Biol Chem. 1993 Oct 15;268(29):21513–21518. [PubMed] [Google Scholar]
  29. Yam J., Frank L., Roberts R. J. Age-related development of pulmonary antioxidant enzymes in the rat. Proc Soc Exp Biol Med. 1978 Feb;157(2):293–296. doi: 10.3181/00379727-157-40040. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES