Skip to main content
PMC home page
Biochemical Journal logoLink to Biochemical Journal
. 1996 Mar 1;314(Pt 2):547–554. doi: 10.1042/bj3140547

Induction of the mammalian stress response gene GADD153 by oxidative stress: role of AP-1 element.

K Z Guyton 1, Q Xu 1, N J Holbrook 1
PMCID: PMC1217084  PMID: 8670069

Abstract

GADD153 is a CCAAT/enhancer-binding-protein-related gene that may function to control cellular growth in response to stress signals. In this study, a variety of oxidant treatments were shown to stimulate endogenous GADD153 mRNA expression and to transcriptionally activate a GADD153 promoter-reporter gene construct in transfected HeLa cells. Both commonalities and distinctions in the induction of GADD153 by H2O2 and the thiol-reactive compound arsenite were demonstrated. GADD153 mRNA induction by both H2O2 and arsenite was potentiated by GSH depletion, and completely inhibited by N-acetyl-cysteine. o-Phenanthroline and mannitol blocked GADD153 induction by H2O2, indicating that iron-generated hydroxyl radical mediates this induction. Concordantly, GSH peroxidase overexpression in WI38 cells attenuated GADD153 mRNA induction by H2O2. However, GADD153 induction by arsenite was only modestly reduced in the same cells, suggesting a lesser contribution of peroxides to gene activation by arsenite. We also demonstrated that oxidative stress participates in the induction of GADD153 by UVC (254 nm) irradiation. Finally, both promoter-deletion analysis and point mutation of the AP-1 site in an otherwise intact promoter support a significant role for AP-1 in transcriptional activation of GADD153 by UVC or oxidant treatment. Indeed, exposure of cells to oxidants or UVC stimulated binding of Fos and Jun to the GADD153 AP-1 element. Together, these results demonstrate that both free-radical generation and thiol modification can transcriptionally activate GADD153, and that AP-1 is critical to oxidative regulation of this gene. This study further supports a role for the GADD153 gene product in the cellular response to oxidant injury.

Full Text

The Full Text of this article is available as a PDF (864.7 KB).

Selected References

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

  1. Alam J., Den Z. Distal AP-1 binding sites mediate basal level enhancement and TPA induction of the mouse heme oxygenase-1 gene. J Biol Chem. 1992 Oct 25;267(30):21894–21900. [PubMed] [Google Scholar]
  2. Barone M. V., Crozat A., Tabaee A., Philipson L., Ron D. CHOP (GADD153) and its oncogenic variant, TLS-CHOP, have opposing effects on the induction of G1/S arrest. Genes Dev. 1994 Feb 15;8(4):453–464. doi: 10.1101/gad.8.4.453. [DOI] [PubMed] [Google Scholar]
  3. Bartlett J. D., Luethy J. D., Carlson S. G., Sollott S. J., Holbrook N. J. Calcium ionophore A23187 induces expression of the growth arrest and DNA damage inducible CCAAT/enhancer-binding protein (C/EBP)-related gene, gadd153. Ca2+ increases transcriptional activity and mRNA stability. J Biol Chem. 1992 Oct 5;267(28):20465–20470. [PubMed] [Google Scholar]
  4. Black H. S. Potential involvement of free radical reactions in ultraviolet light-mediated cutaneous damage. Photochem Photobiol. 1987 Aug;46(2):213–221. doi: 10.1111/j.1751-1097.1987.tb04759.x. [DOI] [PubMed] [Google Scholar]
  5. Carlson S. G., Fawcett T. W., Bartlett J. D., Bernier M., Holbrook N. J. Regulation of the C/EBP-related gene gadd153 by glucose deprivation. Mol Cell Biol. 1993 Aug;13(8):4736–4744. doi: 10.1128/mcb.13.8.4736. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Chakraborti P. K., Garabedian M. J., Yamamoto K. R., Simons S. S., Jr Role of cysteines 640, 656, and 661 in steroid binding to rat glucocorticoid receptors. J Biol Chem. 1992 Jun 5;267(16):11366–11373. [PubMed] [Google Scholar]
  7. Chen Q., Yu K., Holbrook N. J., Stevens J. L. Activation of the growth arrest and DNA damage-inducible gene gadd 153 by nephrotoxic cysteine conjugates and dithiothreitol. J Biol Chem. 1992 Apr 25;267(12):8207–8212. [PubMed] [Google Scholar]
  8. Church G. M., Gilbert W. Genomic sequencing. Proc Natl Acad Sci U S A. 1984 Apr;81(7):1991–1995. doi: 10.1073/pnas.81.7.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. 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]
  10. Delnomdedieu M., Basti M. M., Otvos J. D., Thomas D. J. Transfer of arsenite from glutathione to dithiols: a model of interaction. Chem Res Toxicol. 1993 Sep-Oct;6(5):598–602. doi: 10.1021/tx00035a002. [DOI] [PubMed] [Google Scholar]
  11. Demple B., Amábile-Cuevas C. F. Redox redux: the control of oxidative stress responses. Cell. 1991 Nov 29;67(5):837–839. doi: 10.1016/0092-8674(91)90355-3. [DOI] [PubMed] [Google Scholar]
  12. Devary Y., Gottlieb R. A., Smeal T., Karin M. The mammalian ultraviolet response is triggered by activation of Src tyrosine kinases. Cell. 1992 Dec 24;71(7):1081–1091. doi: 10.1016/s0092-8674(05)80058-3. [DOI] [PubMed] [Google Scholar]
  13. Edgington S. M. As we live and breathe: free radicals and aging. Correlative evidence from a number of fields suggests they may be key. Biotechnology (N Y) 1994 Jan;12(1):37–40. doi: 10.1038/nbt0194-37. [DOI] [PubMed] [Google Scholar]
  14. Fornace A. J., Jr, Nebert D. W., Hollander M. C., Luethy J. D., Papathanasiou M., Fargnoli J., Holbrook N. J. Mammalian genes coordinately regulated by growth arrest signals and DNA-damaging agents. Mol Cell Biol. 1989 Oct;9(10):4196–4203. doi: 10.1128/mcb.9.10.4196. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Friling R. S., Bergelson S., Daniel V. Two adjacent AP-1-like binding sites form the electrophile-responsive element of the murine glutathione S-transferase Ya subunit gene. Proc Natl Acad Sci U S A. 1992 Jan 15;89(2):668–672. doi: 10.1073/pnas.89.2.668. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Gorman C. M., Moffat L. F., Howard B. H. Recombinant genomes which express chloramphenicol acetyltransferase in mammalian cells. Mol Cell Biol. 1982 Sep;2(9):1044–1051. doi: 10.1128/mcb.2.9.1044. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. HARMAN D. Aging: a theory based on free radical and radiation chemistry. J Gerontol. 1956 Jul;11(3):298–300. doi: 10.1093/geronj/11.3.298. [DOI] [PubMed] [Google Scholar]
  18. Holbrook N. J., Luethy J. D., Kin J. Transient expression of foreign genes in lymphoid cells is enhanced by phorbol ester. Mol Cell Biol. 1987 Jul;7(7):2610–2613. doi: 10.1128/mcb.7.7.2610. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Jha A. N., Noditi M., Nilsson R., Natarajan A. T. Genotoxic effects of sodium arsenite on human cells. Mutat Res. 1992 Dec 16;284(2):215–221. doi: 10.1016/0027-5107(92)90005-m. [DOI] [PubMed] [Google Scholar]
  20. Kayanoki Y., Fujii J., Suzuki K., Kawata S., Matsuzawa Y., Taniguchi N. Suppression of antioxidative enzyme expression by transforming growth factor-beta 1 in rat hepatocytes. J Biol Chem. 1994 Jun 3;269(22):15488–15492. [PubMed] [Google Scholar]
  21. Li Y., Jaiswal A. K. Regulation of human NAD(P)H:quinone oxidoreductase gene. Role of AP1 binding site contained within human antioxidant response element. J Biol Chem. 1992 Jul 25;267(21):15097–15104. [PubMed] [Google Scholar]
  22. Luethy J. D., Holbrook N. J. Activation of the gadd153 promoter by genotoxic agents: a rapid and specific response to DNA damage. Cancer Res. 1992 Jan 1;52(1):5–10. [PubMed] [Google Scholar]
  23. 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]
  24. Meyer M., Schreck R., Baeuerle P. A. H2O2 and antioxidants have opposite effects on activation of NF-kappa B and AP-1 in intact cells: AP-1 as secondary antioxidant-responsive factor. EMBO J. 1993 May;12(5):2005–2015. doi: 10.1002/j.1460-2075.1993.tb05850.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Ohba M., Shibanuma M., Kuroki T., Nose K. Production of hydrogen peroxide by transforming growth factor-beta 1 and its involvement in induction of egr-1 in mouse osteoblastic cells. J Cell Biol. 1994 Aug;126(4):1079–1088. doi: 10.1083/jcb.126.4.1079. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. 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]
  27. Park J. S., Luethy J. D., Wang M. G., Fargnoli J., Fornace A. J., Jr, McBride O. W., Holbrook N. J. Isolation, characterization and chromosomal localization of the human GADD153 gene. Gene. 1992 Jul 15;116(2):259–267. doi: 10.1016/0378-1119(92)90523-r. [DOI] [PubMed] [Google Scholar]
  28. Petronilli V., Costantini P., Scorrano L., Colonna R., Passamonti S., Bernardi P. The voltage sensor of the mitochondrial permeability transition pore is tuned by the oxidation-reduction state of vicinal thiols. Increase of the gating potential by oxidants and its reversal by reducing agents. J Biol Chem. 1994 Jun 17;269(24):16638–16642. [PubMed] [Google Scholar]
  29. Prestera T., Holtzclaw W. D., Zhang Y., Talalay P. Chemical and molecular regulation of enzymes that detoxify carcinogens. Proc Natl Acad Sci U S A. 1993 Apr 1;90(7):2965–2969. doi: 10.1073/pnas.90.7.2965. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Schenk H., Klein M., Erdbrügger W., Dröge W., Schulze-Osthoff K. Distinct effects of thioredoxin and antioxidants on the activation of transcription factors NF-kappa B and AP-1. Proc Natl Acad Sci U S A. 1994 Mar 1;91(5):1672–1676. doi: 10.1073/pnas.91.5.1672. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Shi M. M., Kugelman A., Iwamoto T., Tian L., Forman H. J. Quinone-induced oxidative stress elevates glutathione and induces gamma-glutamylcysteine synthetase activity in rat lung epithelial L2 cells. J Biol Chem. 1994 Oct 21;269(42):26512–26517. [PubMed] [Google Scholar]
  32. Shull S., Heintz N. H., Periasamy M., Manohar M., Janssen Y. M., Marsh J. P., Mossman B. T. Differential regulation of antioxidant enzymes in response to oxidants. J Biol Chem. 1991 Dec 25;266(36):24398–24403. [PubMed] [Google Scholar]
  33. Verma A., Hirsch D. J., Glatt C. E., Ronnett G. V., Snyder S. H. Carbon monoxide: a putative neural messenger. Science. 1993 Jan 15;259(5093):381–384. doi: 10.1126/science.7678352. [DOI] [PubMed] [Google Scholar]
  34. Yamanaka K., Hasegawa A., Sawamura R., Okada S. Cellular response to oxidative damage in lung induced by the administration of dimethylarsinic acid, a major metabolite of inorganic arsenics, in mice. Toxicol Appl Pharmacol. 1991 Apr;108(2):205–213. doi: 10.1016/0041-008x(91)90111-q. [DOI] [PubMed] [Google Scholar]
  35. Yao K. S., Xanthoudakis S., Curran T., O'Dwyer P. J. Activation of AP-1 and of a nuclear redox factor, Ref-1, in the response of HT29 colon cancer cells to hypoxia. Mol Cell Biol. 1994 Sep;14(9):5997–6003. doi: 10.1128/mcb.14.9.5997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Zhan Q., Lord K. A., Alamo I., Jr, Hollander M. C., Carrier F., Ron D., Kohn K. W., Hoffman B., Liebermann D. A., Fornace A. J., Jr The gadd and MyD genes define a novel set of mammalian genes encoding acidic proteins that synergistically suppress cell growth. Mol Cell Biol. 1994 Apr;14(4):2361–2371. doi: 10.1128/mcb.14.4.2361. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society

RESOURCES