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. 1999 Apr 15;339(Pt 2):335–341.

Positive and negative regulatory elements in the upstream region of the rat Cu/Zn-superoxide dismutase gene.

M S Chang 1, H Y Yoo 1, H M Rho 1
PMCID: PMC1220162  PMID: 10191264

Abstract

Cu/Zn-superoxide dismutase (SOD1) catalyses the dismutation of superoxide radicals and neutralizes the oxidative effects of various chemicals. Deletion analysis of the upstream region of the rat SOD1 gene revealed that the promoter contains a positive regulatory element (PRE) and a negative regulatory element (NRE), which encompass the regions from -576 to -412 and from -412 to -305 respectively from the site of initiation of transcription. These DNA elements showed enhancer and silencer activities respectively in the natural context and in a heterologous promoter system. Using an electrophoretic-mobility-shift assay and a supershift assay with a specific antibody, the cis-elements of the PRE and NRE were identified as binding sites for transcription factors Elk1 and YY1 (Ying-Yang 1) respectively. Consistent with the presumed roles of the PRE and NRE, Elk1 increased SOD1 gene transcription about 4-5-fold, whereas YY1 exerted a negative effect of about 6-fold. Mutations of the Elk1- and YY1-binding sites led to diminution and elevation respectively of transcriptional activities, both in the natural context and in heterologous promoter systems. These results suggest that the transcription factors Elk1 and YY1, binding in the PRE and NRE respectively, co-ordinate the expression of the SOD1 gene.

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Selected References

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  1. Asayama K., Burr I. M. Rat superoxide dismutases. Purification, labeling, immunoassay, and tissue concentration. J Biol Chem. 1985 Feb 25;260(4):2212–2217. [PubMed] [Google Scholar]
  2. Bauknecht T., Angel P., Royer H. D., zur Hausen H. Identification of a negative regulatory domain in the human papillomavirus type 18 promoter: interaction with the transcriptional repressor YY1. EMBO J. 1992 Dec;11(12):4607–4617. doi: 10.1002/j.1460-2075.1992.tb05563.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Belaguli N. S., Schildmeyer L. A., Schwartz R. J. Organization and myogenic restricted expression of the murine serum response factor gene. A role for autoregulation. J Biol Chem. 1997 Jul 18;272(29):18222–18231. doi: 10.1074/jbc.272.29.18222. [DOI] [PubMed] [Google Scholar]
  4. Brady T. C., Chang L. Y., Day B. J., Crapo J. D. Extracellular superoxide dismutase is upregulated with inducible nitric oxide synthase after NF-kappa B activation. Am J Physiol. 1997 Nov;273(5 Pt 1):L1002–L1006. doi: 10.1152/ajplung.1997.273.5.L1002. [DOI] [PubMed] [Google Scholar]
  5. Bushmeyer S., Park K., Atchison M. L. Characterization of functional domains within the multifunctional transcription factor, YY1. J Biol Chem. 1995 Dec 15;270(50):30213–30220. doi: 10.1074/jbc.270.50.30213. [DOI] [PubMed] [Google Scholar]
  6. Carey M. The enhanceosome and transcriptional synergy. Cell. 1998 Jan 9;92(1):5–8. doi: 10.1016/s0092-8674(00)80893-4. [DOI] [PubMed] [Google Scholar]
  7. Ceballos I., Lafon M., Javoy-Agid F., Hirsch E., Nicole A., Sinet P. M., Agid Y. Superoxide dismutase and Parkinson's disease. Lancet. 1990 Apr 28;335(8696):1035–1036. doi: 10.1016/0140-6736(90)91099-v. [DOI] [PubMed] [Google Scholar]
  8. Chen C. A., Okayama H. Calcium phosphate-mediated gene transfer: a highly efficient transfection system for stably transforming cells with plasmid DNA. Biotechniques. 1988 Jul-Aug;6(7):632–638. [PubMed] [Google Scholar]
  9. Cohen P. The role of protein phosphorylation in neural and hormonal control of cellular activity. Nature. 1982 Apr 15;296(5858):613–620. doi: 10.1038/296613a0. [DOI] [PubMed] [Google Scholar]
  10. Dignam J. D., Lebovitz R. M., Roeder R. G. Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res. 1983 Mar 11;11(5):1475–1489. doi: 10.1093/nar/11.5.1475. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Duchesne J. A unifying biochemical theory of cancer, senescence and maximal life span. J Theor Biol. 1977 May 7;66(1):137–145. doi: 10.1016/0022-5193(77)90316-2. [DOI] [PubMed] [Google Scholar]
  12. Flanagan J. R., Becker K. G., Ennist D. L., Gleason S. L., Driggers P. H., Levi B. Z., Appella E., Ozato K. Cloning of a negative transcription factor that binds to the upstream conserved region of Moloney murine leukemia virus. Mol Cell Biol. 1992 Jan;12(1):38–44. doi: 10.1128/mcb.12.1.38. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Fridovich I. Superoxide dismutases. Annu Rev Biochem. 1975;44:147–159. doi: 10.1146/annurev.bi.44.070175.001051. [DOI] [PubMed] [Google Scholar]
  14. Gerdin E., Tydén O., Eriksson U. J. The development of antioxidant enzymatic defense in the perinatal rat lung: activities of superoxide dismutase, glutathione peroxidase, and catalase. Pediatr Res. 1985 Jul;19(7):687–691. doi: 10.1203/00006450-198507000-00010. [DOI] [PubMed] [Google Scholar]
  15. 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]
  16. Gralla E. B., Thiele D. J., Silar P., Valentine J. S. ACE1, a copper-dependent transcription factor, activates expression of the yeast copper, zinc superoxide dismutase gene. Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8558–8562. doi: 10.1073/pnas.88.19.8558. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hardmeier R., Hoeger H., Fang-Kircher S., Khoschsorur A., Lubec G. Transcription and activity of antioxidant enzymes after ionizing irradiation in radiation-resistant and radiation-sensitive mice. Proc Natl Acad Sci U S A. 1997 Jul 8;94(14):7572–7576. doi: 10.1073/pnas.94.14.7572. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hariharan N., Kelley D. E., Perry R. P. Delta, a transcription factor that binds to downstream elements in several polymerase II promoters, is a functionally versatile zinc finger protein. Proc Natl Acad Sci U S A. 1991 Nov 1;88(21):9799–9803. doi: 10.1073/pnas.88.21.9799. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Hass M. A., Massaro D. Developmental regulation of rat lung Cu,Zn-superoxide dismutase. Biochem J. 1987 Sep 15;246(3):697–703. doi: 10.1042/bj2460697. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Hipskind R. A., Rao V. N., Mueller C. G., Reddy E. S., Nordheim A. Ets-related protein Elk-1 is homologous to the c-fos regulatory factor p62TCF. Nature. 1991 Dec 19;354(6354):531–534. doi: 10.1038/354531a0. [DOI] [PubMed] [Google Scholar]
  21. Kim H. T., Kim Y. H., Nam J. W., Lee H. J., Rho H. M., Jung G. Study of 5'-flanking region of human Cu/Zn superoxide dismutase. Biochem Biophys Res Commun. 1994 Jun 30;201(3):1526–1533. doi: 10.1006/bbrc.1994.1877. [DOI] [PubMed] [Google Scholar]
  22. Kim T. K., Maniatis T. The mechanism of transcriptional synergy of an in vitro assembled interferon-beta enhanceosome. Mol Cell. 1997 Dec;1(1):119–129. doi: 10.1016/s1097-2765(00)80013-1. [DOI] [PubMed] [Google Scholar]
  23. Kim Y. H., Park K. H., Rho H. M. Transcriptional activation of the Cu,Zn-superoxide dismutase gene through the AP2 site by ginsenoside Rb2 extracted from a medicinal plant, Panax ginseng. J Biol Chem. 1996 Oct 4;271(40):24539–24543. doi: 10.1074/jbc.271.40.24539. [DOI] [PubMed] [Google Scholar]
  24. Kim Y. H., Yoo H. Y., Chang M. S., Jung G., Rho H. M. C/EBP alpha is a major activator for the transcription of rat Cu/Zn superoxide dismutase gene in liver cell. FEBS Lett. 1997 Jan 20;401(2-3):267–270. doi: 10.1016/s0014-5793(96)01487-1. [DOI] [PubMed] [Google Scholar]
  25. Kim Y. H., Yoo H. Y., Jung G., Kim J. Y., Rho H. M. Isolation and analysis of the rat genomic sequence encoding Cu/Zn superoxide dismutase. Gene. 1993 Nov 15;133(2):267–271. doi: 10.1016/0378-1119(93)90650-r. [DOI] [PubMed] [Google Scholar]
  26. Kong X. J., Fanburg B. L. Regulation of Cu,Zn-superoxide dismutase in bovine pulmonary artery endothelial cells. J Cell Physiol. 1992 Dec;153(3):491–497. doi: 10.1002/jcp.1041530308. [DOI] [PubMed] [Google Scholar]
  27. Lee J. S., Galvin K. M., See R. H., Eckner R., Livingston D., Moran E., Shi Y. Relief of YY1 transcriptional repression by adenovirus E1A is mediated by E1A-associated protein p300. Genes Dev. 1995 May 15;9(10):1188–1198. doi: 10.1101/gad.9.10.1188. [DOI] [PubMed] [Google Scholar]
  28. Levanon D., Lieman-Hurwitz J., Dafni N., Wigderson M., Sherman L., Bernstein Y., Laver-Rudich Z., Danciger E., Stein O., Groner Y. Architecture and anatomy of the chromosomal locus in human chromosome 21 encoding the Cu/Zn superoxide dismutase. EMBO J. 1985 Jan;4(1):77–84. doi: 10.1002/j.1460-2075.1985.tb02320.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Liang H. C., Shertzer H. G., Nebert D. W. "Oxidative stress" response in liver of an untreated newborn mouse having a 1.2-centimorgan deletion on chromosome 7. Biochem Biophys Res Commun. 1992 Feb 14;182(3):1160–1165. doi: 10.1016/0006-291x(92)91853-i. [DOI] [PubMed] [Google Scholar]
  30. Liu R., Baillie J., Sissons J. G., Sinclair J. H. The transcription factor YY1 binds to negative regulatory elements in the human cytomegalovirus major immediate early enhancer/promoter and mediates repression in non-permissive cells. Nucleic Acids Res. 1994 Jul 11;22(13):2453–2459. doi: 10.1093/nar/22.13.2453. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Luckow B., Schütz G. CAT constructions with multiple unique restriction sites for the functional analysis of eukaryotic promoters and regulatory elements. Nucleic Acids Res. 1987 Jul 10;15(13):5490–5490. doi: 10.1093/nar/15.13.5490. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Margolis D. M., Somasundaran M., Green M. R. Human transcription factor YY1 represses human immunodeficiency virus type 1 transcription and virion production. J Virol. 1994 Feb;68(2):905–910. doi: 10.1128/jvi.68.2.905-910.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Marklund S. L. Extracellular superoxide dismutase and other superoxide dismutase isoenzymes in tissues from nine mammalian species. Biochem J. 1984 Sep 15;222(3):649–655. doi: 10.1042/bj2220649. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. 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]
  35. Montalvo E. A., Shi Y., Shenk T. E., Levine A. J. Negative regulation of the BZLF1 promoter of Epstein-Barr virus. J Virol. 1991 Jul;65(7):3647–3655. doi: 10.1128/jvi.65.7.3647-3655.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Nishizuka Y. Studies and perspectives of protein kinase C. Science. 1986 Jul 18;233(4761):305–312. doi: 10.1126/science.3014651. [DOI] [PubMed] [Google Scholar]
  37. Price M. A., Rogers A. E., Treisman R. Comparative analysis of the ternary complex factors Elk-1, SAP-1a and SAP-2 (ERP/NET). EMBO J. 1995 Jun 1;14(11):2589–2601. doi: 10.1002/j.1460-2075.1995.tb07257.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Rao G. N., Lasségue B., Griendling K. K., Alexander R. W., Berk B. C. Hydrogen peroxide-induced c-fos expression is mediated by arachidonic acid release: role of protein kinase C. Nucleic Acids Res. 1993 Mar 11;21(5):1259–1263. doi: 10.1093/nar/21.5.1259. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Rosen D. R., Siddique T., Patterson D., Figlewicz D. A., Sapp P., Hentati A., Donaldson D., Goto J., O'Regan J. P., Deng H. X. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature. 1993 Mar 4;362(6415):59–62. doi: 10.1038/362059a0. [DOI] [PubMed] [Google Scholar]
  40. Saggu H., Cooksey J., Dexter D., Wells F. R., Lees A., Jenner P., Marsden C. D. A selective increase in particulate superoxide dismutase activity in parkinsonian substantia nigra. J Neurochem. 1989 Sep;53(3):692–697. doi: 10.1111/j.1471-4159.1989.tb11759.x. [DOI] [PubMed] [Google Scholar]
  41. Seo S. J., Kim H. T., Cho G., Rho H. M., Jung G. Sp1 and C/EBP-related factor regulate the transcription of human Cu/Zn SOD gene. Gene. 1996 Oct 31;178(1-2):177–185. doi: 10.1016/0378-1119(96)00383-6. [DOI] [PubMed] [Google Scholar]
  42. Shaw P. E. Ternary complex formation over the c-fos serum response element: p62TCF exhibits dual component specificity with contacts to DNA and an extended structure in the DNA-binding domain of p67SRF. EMBO J. 1992 Aug;11(8):3011–3019. doi: 10.1002/j.1460-2075.1992.tb05371.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Shi Y., Seto E., Chang L. S., Shenk T. Transcriptional repression by YY1, a human GLI-Krüppel-related protein, and relief of repression by adenovirus E1A protein. Cell. 1991 Oct 18;67(2):377–388. doi: 10.1016/0092-8674(91)90189-6. [DOI] [PubMed] [Google Scholar]
  44. Shrivastava A., Saleque S., Kalpana G. V., Artandi S., Goff S. P., Calame K. Inhibition of transcriptional regulator Yin-Yang-1 by association with c-Myc. Science. 1993 Dec 17;262(5141):1889–1892. doi: 10.1126/science.8266081. [DOI] [PubMed] [Google Scholar]
  45. Stein B., Rahmsdorf H. J., Steffen A., Litfin M., Herrlich P. UV-induced DNA damage is an intermediate step in UV-induced expression of human immunodeficiency virus type 1, collagenase, c-fos, and metallothionein. Mol Cell Biol. 1989 Nov;9(11):5169–5181. doi: 10.1128/mcb.9.11.5169. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Tanswell A. K., Freeman B. A. Pulmonary antioxidant enzyme maturation in the fetal and neonatal rat. I. Developmental profiles. Pediatr Res. 1984 Jul;18(7):584–587. doi: 10.1203/00006450-198407000-00003. [DOI] [PubMed] [Google Scholar]
  47. Treisman R. Ternary complex factors: growth factor regulated transcriptional activators. Curr Opin Genet Dev. 1994 Feb;4(1):96–101. doi: 10.1016/0959-437x(94)90097-3. [DOI] [PubMed] [Google Scholar]

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