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

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

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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. Access through your institution Buy or subscribe This is a preview of subscription content,


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DISEASE Article Open access 18 February 2021 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 


Download references 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. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * 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 * Department of Neurology,


University of Kentucky, Lexington, 40536-0305, Kentucky, USA Yong Xu, Anuradha Krishnan, X Steven Wan, Hideyuki Majima & Edward J Kasarskis Authors * Yong Xu View author publications You


can also search for this author inPubMed Google Scholar * Anuradha Krishnan View author publications You can also search for this author inPubMed Google Scholar * X Steven Wan View author


publications You can also search for this author inPubMed Google Scholar * Hideyuki Majima View author publications You can also search for this author inPubMed Google Scholar * Che-Chung


Yeh View author publications You can also search for this author inPubMed Google Scholar * Gabriele Ludewig View author publications You can also search for this author inPubMed Google


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author inPubMed Google Scholar RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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 Download citation *


Received: 20 April 1998 * Revised: 02 July 1998 * Accepted: 03 July 1998 * Published: 19 January 1999 * Issue Date: 07 January 1999 * DOI: https://doi.org/10.1038/sj.onc.1202265 SHARE THIS


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Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * tumor suppressor gene * mutation * promoter * transcription factors * MnSOD * reactive oxygen species