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  • Original Paper
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Mutations in the promoter reveal a cause for the reduced expression of the human manganese superoxide dismutase gene in cancer cells

Oncogene volume 18, pages 93–102 (1999)Cite this article

Abstract

Manganese superoxide dismutase (MnSOD) has been shown to play an important role in preventing the development of cancer. MnSOD activity is reduced in many transformed cells and tumor tissues. We previously showed that the reduced level of MnSOD activity in cancer cells was not due to a defect in the primary structure of MnSOD protein, but rather was due to defects in gene expression. To elucidate the cause for the reduced expression of human MnSOD in cancer, we investigated the nucleotide sequence in the regulatory region of the MnSOD gene in a normal human cell line and various human tumor cell lines. A DNA fragment spanning 3.4 kb 5′ flanking region of the MnSOD gene isolated from a normal human genomic DNA library was used to determine the DNA sequence of MnSOD promoter. PCR primers were used for amplification of the 3.4 kb 5′ flanking region of the human MnSOD gene in cancer cells. Sequence analysis identified three heterozygous mutations in the proximal region of the promoter in five human tumor cell lines. These mutations, clustered around the GC-rich region of the human MnSOD promoter, change the binding pattern of AP-2 and lead to a reduction in transcription activity using a luciferase reporter assay system. These results suggest that the reduced level of MnSOD expression in some tumor cells is, at least in part, due to a defect in the DNA sequence of the promoter region.

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References

  • Amstad PA, Liu H, Ichimiya M, Berezesky IK and Trump BF. . 1997 Carcinogenesis 18: 479–484.

  • Baker DL, Dave V, Reed T and Periasamy M. . 1996 J. Biol. Chem. 271: 5921–5928.

    Article  CAS  Google Scholar 

  • Briggs MR, Kadonaga JT, Bell SP and Tjian R. . 1986 Science 234: 47–52.

    Article  CAS  Google Scholar 

  • Church SL, Grant JW, Ridnour LA, Oberley LW, Swanson PE, Meltzer PS and Trent JM. . 1993 Proc. Natl. Acad. Sci. USA 90: 3113–3117.

  • Cohen HT, Bossone SA, Zhu G and McDonald GA. . 1997 J. Biol. Chem. 272: 2901–2913.

    Article  CAS  Google Scholar 

  • Courey AJ and Tjian R. . 1988 Cell 55: 887–898.

    Article  CAS  Google Scholar 

  • Dharmavaram RM, Liu G, Mowers SD and Jimenez SA. . 1997 J. Biol. Chem. 272: 26918–26925.

    Article  CAS  Google Scholar 

  • Dynan WS and Tjian R. . 1983 Cell 32: 669–680.

    Article  CAS  Google Scholar 

  • Dynan WS and Tjian R. . 1985 Nature 316: 774–778.

    Article  CAS  Google Scholar 

  • Flaman JM, Frebourg T, Moreau V, Charbonnier F, Martin C, Ishioka C, Friend SH and Iggo, R. . 1994 Nucleic Acids Res. 22: 3259–3260.

  • Getman DK, Mutero A, Inoue K and Taylor P. . 1995 J. Biol. Chem. 270: 23511–23519.

    Article  CAS  Google Scholar 

  • Halliwell B and Gutteridge JMC. . 1989 Free Radicals in Biology and Medicine. 2nd Edition Clarendon Press: Oxford. pp. 86–123.

    Google Scholar 

  • Ho YS, Howard AJ, and Crapo JD. . 1991 Am. J. Respir. Cell. Mol. Biol. 4: 278–286.

  • Ikeda K, Nagano K and Kawakami K. . 1993 Gene 136: 341–343.

    Article  Google Scholar 

  • Innis MA, Myambo KB, Gelfand DH and Brow MAD. . 1988 Proc. Natl. Acad. Sci. USA 85: 9436–9440.

  • Jones KA, Yamamoto KR and Tjian R. . 1985 Cell 42: 559–572.

    Article  CAS  Google Scholar 

  • Jones PL, Kucera G, Gordon H and Boss JM. . 1995 Gene 153: 155–161.

    Article  CAS  Google Scholar 

  • Kadonaga JT, Courey AJ, Ladika J and Tjian R. . 1988 Science 242: 1566–1570.

    Article  CAS  Google Scholar 

  • Keller JN, Kindy MS, Holtsberg FW, St.Clair DK, Yen H-C, Germeyer A, Steiner SM, Bruce-Keller AJ, Hutchins JB and Mattson MP. . 1998 J. Neurosci. 18: 687–697.

    Article  CAS  Google Scholar 

  • Lee W, Haslinger A, Karin M and Tjian R . 1987 Nature 325: 368–372.

    Article  CAS  Google Scholar 

  • Li JJ, Oberley LW, St.Clair DK, Ridnour LA and Oberley TD. . 1995 Oncogene 10: 1989–2000.

  • Li M, Pullano R, Yang HL, Lee HK, Miyamoto NG, Filmus J and Buick RN. . 1997 Oncogene 15: 1535–1544.

    Article  CAS  Google Scholar 

  • López-Rodríguez C, Botella L and Corbí AL. . 1997 J. Biol. Chem. 272: 29120–29126.

    Article  Google Scholar 

  • Marklund SL. . 1982 Proc. Natl. Acad. Sci. USA 79: 7634–7638.

  • McCord JM and Fridovich IJ. . 1969 J. Biol. Chem. 244: 6049–6055.

  • Meyrick B and Magnuson MA. . 1994 Am. J. Respir. Cell Mol. Biol. 10: 113–121.

  • Mitchell PJ, Timmons PM, Hébert JM, Rigby PWJ and Tjian R. . 1991 Genes & Dev. 5: 105–119.

  • Mitchell PJ, Wang C and Tjian R. . 1987 Cell 50: 847–861.

    Article  CAS  Google Scholar 

  • Moffat GJ, McLaren AW and Wolf CR. . 1996 J. Biol. Chem. 271: 1054–1060.

    Article  CAS  Google Scholar 

  • Oberley LW and Buettner GR. . 1979 Cancer Res. 39: 1141–1149.

  • Oberley LW and Oberley TD. . 1984 J. Theor. Biol. 106: 403–422.

  • Oberley LW, McCormick ML, Sierra-Rivera E and St.Clair DK. . 1989 Free Radic. Biol. Med. 6: 379–384.

  • Perkins ND, Edwards NL, Duckett CS, Agranoff AB, Schmid RM and Nabel GJ. . 1993 EMBO J. 12: 3551–3558.

  • Safford SE, Oberley TD, Urano M and St.Clair DK. . 1994 Cancer Res. 54: 4261–4265.

  • Sanger F, Nicklen S and Coulson AR. . 1977 Proc. Natl. Acad. Sci. USA 74: 5463–5467.

  • St.Clair DK. . 1997 Oncol. Rep. 3: 429–432.

  • St.Clair DK and Holland JC. . 1991 Cancer Res. 51: 939–943.

  • St.Clair DK, Oberley TD, Muse KE, and St.Clair WH. . 1994 Free Radic. Biol. Med. 16: 275–282.

  • St.Clair DK, Wan XS, Kuroda M, Vichitbandha S, Tsuchida, E and Urano M. . 1997 Oncol. Rep. 4: 753–757.

  • St.Clair DK, Wan XS, Oberley TD, Muse KE, and St.Clair WH. . 1992 Mol. Carcinogenesis 6: 238–242.

  • Su W, Jackson S, Tjian R and Echols H. . 1991 Genes & Dev. 5: 820–826.

  • Tang W, Keesler GA and Tabas I. . 1997 J. Biol. Chem. 272: 13146–13151.

    Article  CAS  Google Scholar 

  • Thomsen DR, Stenberg RM, Goins WF and Stinski MF. . 1984 Proc. Natl. Acad. Sci. USA 81: 659–663.

  • Trent JM, Stanbridge EJ, McBride HL, Meese EU, Casey G, Araujo DE, Witkowki CM and Nagle RB. . 1990 Science 247: 568–571.

    Article  CAS  Google Scholar 

  • Urano M, Kuroda M, Reynolds R, Oberley TD and St.Clair DK. . 1995 Cancer Res. 55: 2490–2493.

  • Wan XS, Devalaraja MN and St.Clair DK. . 1994 DNA Cell Biol. 13: 1127–1136.

  • Weisiger RA and Fridovich IJ. . 1973 J. Biol. Chem. 248: 4793–4796.

  • Wigler M, Silverstein S, Lee L-S, Pellicer A, Cheng Y-C and Axel R. . (1977), Cell 11: 223–232.

    Article  CAS  Google Scholar 

  • Williams T, Admon A, Lüscher B and Tjian R. . 1988 Genes & Dev. 2: 1557–1569.

  • Wispe JR, Warner BB, Clark JC, Dey CR, Neuman J, Glasser SW, Crapo JD, Chang L-Y and Whitsett JA. . 1992 J. Biol. Chem. 267: 23937–23941.

  • Yen H-C, Oberley TD, Vichitbandha S, Ho Y-S and St.Clair DK. . 1996 J. Clin. Invest. 98: 1253–1260.

    Article  CAS  Google Scholar 

  • Yen H-C and St.Clair DK. . 1997 J. Biomed. Lab. Sci. 9: 40–54.

  • Zhong W, Oberley LW, Oberley TD and St.Clair DK. . 1997 Oncogene 14: 481–490.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Dr H-C Yen for statistical assistance. This work was supported by NIH grants CA 49797, CA 59835, and HL 03544, and grants from the American Heart association and the Environmental Protection Agency to DK St.Clair.

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Authors and Affiliations

  1. Graduate Center for Toxicology, University of Kentucky, Lexington, 40536-0305, Kentucky, USA

    Yong Xu, Anuradha Krishnan, X Steven Wan, Hideyuki Majima, Che-Chung Yeh, Gabriele Ludewig, Edward J Kasarskis & Daret K St.Clair

  2. Department of Neurology, University of Kentucky, Lexington, 40536-0305, Kentucky, USA

    Yong Xu, Anuradha Krishnan, X Steven Wan, Hideyuki Majima & Edward J Kasarskis

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  1. Yong Xu
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Xu, Y., Krishnan, A., Wan, X. et al. Mutations in the promoter reveal a cause for the reduced expression of the human manganese superoxide dismutase gene in cancer cells. Oncogene 18, 93–102 (1999). https://doi.org/10.1038/sj.onc.1202265

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