Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Human Dkk-1, a gene encoding a Wnt antagonist, responds to DNA damage and its overexpression sensitizes brain tumor cells to apoptosis following alkylation damage of DNA

Abstract

The human Dkk-1 (hDkk-1) gene, a transcriptional target of the p53 tumor suppressor, encodes a powerful inhibitor of the Wnt signaling pathway and regulates the spatial patterning/morphogenesis of the mammalian central nervous system. We investigated the p53-related functions of the hDkk-1 gene by studying its response to DNA damage and its modulation of apoptosis in human glioma cells. Various chemotherapeutic and other agents that induce DNA adducts and compromise its integrity (1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), cisplatin, H2O2 and UV rays) enhanced the expression of hDkk-1 significantly. The damage-induced increase in hDkk-1 mRNA levels occurred in many human tumor cell lines, irrespective of their p53 gene status. The human glioblastoma cell line, U87MG, which had undetectable hDkk-1 expression, was engineered to express moderate levels of the hDkk protein by stable transfection. The engineered cells did not show any morphological changes, but underwent marked apoptosis after ceramide treatment. Further, the DNA cross-linking drugs BCNU and cisplatin, but not the microtubule poison vincristine, induced significant cell death in U87MG/hDkk cells, and this was accompanied by altered Bcl-2/Bax expression and a reduction in the amount of telomere DNA as visualized by fluorescence in situ hybridization. These results show that hDkk-1 is a pro-apoptotic gene and suggest that it may play important roles in linking the oncogenic Wnt and p53 tumor suppressor pathways.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9

Similar content being viewed by others

Abbreviations

APC:

adenomatous polyposis coli

BCNU:

1,3-bis(2-chloroethyl)-1-nitrosourea

FISH:

fluorescence in situ hybridization

GSK3:

glycogen synthase kinase 3

hDkk-1:

human Dkk-1

References

  • Ausubel FM, Brent R, Kingston RE, Moore DD, Smith JA, Seidman JG, Struhl K (eds) . 1987 Current Protocols in Molecular Biology New York: Wiley Interscience

    Google Scholar 

  • Barker N, Morin PJ, Clevers H . 2000 Adv. Cancer Res. 77: 1–24

  • Burger AM, Double JA, Newell DR . 1997 Eur. J. Cancer 33: 638–644

  • Burkhart BA, Alcorta DA, Chiao C, Isaacs JS, Barrett JC . 1999 Exp. Cell Res. 247: 168–175

  • Chen S, Guttridge DC, You Z, Zhang Z, Fribley A, Mayo MW, Kitajewski J, Wang C-Y . 2001 J. Cell Biol. 152: 87–96

  • Dale TC . 1998 Biochem. J. 329: 209–223

  • De Lange T . 1995 Telomere dynamics and genome instability in human cancer Telomeres Cold Spring Harbor, NY: Cold Spring Harbor Press pp 265–293

    Google Scholar 

  • Deng Y, Wu X . 2000 Proc. Natl. Acad. Sci. USA 97: 12050–12055

  • Downing KH . 2000 Annu. Rev. Cell Dev. Biol. 16: 89–111

  • Fedi P, Bafico A, Nieto Soria A, Burgess WH, Miki T, Bottaro DP, Kraus MH, Aaronson SA . 1999 J. Biol. Chem. 274: 19465–19472

  • Finch PW, He X, Kelley MJ, Uren A, Schaudies RP, Popescu NC, Rudikoff S, Aaronson SA, Varmus HE, Rubin JS . 1997 Proc. Natl. Acad. Sci. USA 94: 6770–6775

  • Glinka A, Wu W, Delius H, Monaghan AP, Blumenstock C, Niehrs C . 1998 Nature 391: 357–362

  • Hannun YA . 1996 Science 274: 1855–1859

  • Hannun YA, Luberto C . 2000 Trends Cell Biol. 10: 73–80

  • Hart MJ, de los Santos R, Albert IN, Rubinfeld B, Polakis P . 1998 Curr. Biol. 8: 573–581

  • Hayashi S, Rubinfeld B, Souza B, Polakis P, Wieschaus E, Levine AJ . 1997 Proc. Natl. Acad. Sci. USA 94: 242–247

  • Henriksson M, Selivanova G, Lindstrom M, Wiman KG . 2001 Apoptosis 6: 133–137

  • Howe LR, Subbaramaiah K, Chung WJ, Dannenberg AJ, Brown AM . 1999 Cancer Res. 59: 1572–1577

  • Ishii K, Yang W-L, Cvijic ME, Kikuchi Y, Nagata I, Chin K-V . 2000 Exp. Cell Res. 255: 95–101

  • Ishibashi T, Lippard SJ . 1998 Proc. Natl. Acad. Sci. USA 95: 4219–4223

  • Israeli D, Tessler E, Haupt Y, Elkeles A, Wilder S, Amson R, Telerman A, Oren M . 1997 EMBO J. 16: 4384–4392

  • Jaiswal AS, Narayan S . 2001 J. Biol. Chem. 276: 18193–18199

  • Jayadev S, Liu B, Bielawska AE, Lee JY, Nazaire F, Pushkareva MY, Obeid LM, Hannun YA . 1995 J. Biol. Chem. 270: 2047–2052

  • Jimenez GS, Khan SH, Stommel JM, Wahl GM . 1999 Oncogene 18: 7656–7665

  • Johnson M, Dimitrov D, Vojta P, Barrett JC, Noda A, Pereira-Smith OM, Smith JR . 1994 Mol. Carcinog. 11: 59–64

  • Kanaya T, Kyo S, Hamada K, Takakura M, Kitagawa Y, Harada H, Inoue M . 2000 Clin. Cancer Res. 6: 1239–1247

  • Kazanskaya O, Glinka A, Niehrs C . 2000 Development 127: 4981–4992

  • Kruk PA, Rampino NJ, Bohr VA . 1995 Proc. Natl. Acad. Sci. USA 92: 258–262

  • Krupnik VE, Sharp JD, Jiang C, Robison K, Chickering TW, Amaravadi L, Brown DE, Guyot D, Mays G, Leiby K, Chang B, Duong T, Goodearl AD, Gearing DP, Sokol SY, McCarthy SA . 1999 Gene 238: 301–313

  • Leyns L, Bouwmester T, Kim SH, Piccolo S, De Robertis EM . 1997 Cell 88: 747–756

  • Mao B, Wu W, Li Y, Hoppe D, Stannek P, Glinka A, Niehrs C . 2001 Nature 411: 255–256

  • McGrew LL, Takemaru K, Bates R, Moon RT . 1999 Mech. Dev. 87: 21–32

  • Melkonyan HS, Chang WC, Shapiro JP, Mahadevappa M, Fitzpatrick PA, Kiefer MC, Tomei LD, Umansky SR . 1997 Proc. Natl. Acad. Sci. USA 94: 13636–13641

  • Miyagishi M, Fuji R, Hatta M, Yoshida E, Araya N, Nagafuchi A, Ishihara S, Nakajima T, Fukamizu A . 2000 J. Biol. Chem. 275: 35170–35175

  • Molenaar M, Destree O . 1999 Int. J. Dev. Biol. 43: 675–680

  • Moon RT, Brown JD, Yang-Snyder JA, Miller JR . 1997 Cell 88: 725–728

  • Multani AS, Chandra J, McConkey DJ, Sen S, Cabral TF, Pathak S . 1999 Oncol Res. 11: 455–460

  • Multani AS, Ozer M, Narayan S, Kumar V, Chandra J, McConkey D, Newman RA, Pathak S . 2000 Neoplasia 2: 339–345

  • Mukhopadhyay T, Multani AS, Roth JA, Pathak S . 1998 Oncogene 17: 901–906

  • Nagele RG, Velasco AQ, Anderson WJ, McMahon DJ, Thomson Z, Fazekas J, Wind K, Lee H-Y . 2001 J. Cell Sci. 114: 377–388

  • Naylor S, Smalley MJ, Robertson D, Gusterson BA, Edwards PA, Dale TC . 2000 J. Cell Sci. 113: 2129–2138

  • Nusse R . 2001 Nature 411: 255–256

  • Pathak S . 1976 J. Reprod. Med. 17: 25–28

  • Polakis P . 2000 Genes Dev. 14: 1837–1851

  • Robertson JD, Orrenius B . 2000 Crit. Rev. Toxicol. 30: 609–627

  • Roth W, Wild-Bode C, Platten M, Grimmel C, Melkonyan HS, Dichgans J, Weller M . 2000 Oncogene 19: 4210–4220

  • Sadot E, Geiger B, Oren M, Ben-Ze'ev A . 2001 Mol. Cell. Biol. 21: 6768–6781

  • Sakanaka C, Weiss JB, Williams LT . 1998 Proc. Natl. Acad. Sci. USA 95: 3020–3023

  • Sawada M, Nakashima S, Kiyono T, Nakagawa M, Yamada J, Yamakawa H, Banno Y, Shinoda J, Nishimura Y, Nozawa Y . 2001 Oncogene 20: 1368–1378

  • Schneider VA, Mercola M . 2001 Genes Dev. 15: 304–315

  • Scotting PJ, Thompson SL, Punt JA, Walker DA . 2000 Childs Nerv. Syst. 16: 261–267

  • Senchenkov A, Litvak DA, Cabot MC . 2001 J. Natl. Cancer Inst. 93: 347–357

  • Shimizu H, Julius MA, Giarre M, Zheng Z, Brown AM, Kitajewski J . 1997 Cell Growth Differ. 8: 1349–1358

  • Shutman M, Zhurinsky J, Simcha I, Albanese C, D'Amico M, Petsell RG, Ben-Ze'ev A . 1999 Proc. Natl. Acad. Sci. USA 96: 5522–5527

  • Srivenugopal KS, Ali-Osman F . 1997 Int. J. Oncol. 11: 1251–1256

  • Srivenugopal KS, Ali-Osman F . 1996 Proc. Amer. Assoc. Cancer Res. 37: p 5

  • Srivenugopal KS, Ali-Osman F . 1990 Biochem. Pharmacol. 40: 473–479

  • Tate G, Mitsuya T . 1999 J. Biochem. Mol. Biol. Biophys. 3: 239–242

  • Tetsu O, McCormick F . 1999 Nature 398: 422–426

  • Turenne GA, Price BD . 2001 BMC Cell Biol. 2: 12–16

  • Ueda Y, Hijikata M, Takagi S, Takada R, Takada S, Chiba T, Shimotohno K . 2001 Biochem. Biophys. Res. Commun. 283: 327–333

  • Van Meir EG, Kikuchi T, Tada M, Li H, Diserens AC, Wojcik BE, Huang HJ, Friedman T, de Tribolet N, Cavanee WK . 1994 Cancer Res. 54: 649–652

  • Wang J, Shou J, Chen X . 2000 Oncogene 19: 1843–1848

  • Wodarz A, Nusse R . 1998 Annu. Rev. Cell. Dev. Biol. 14: 59–88

  • Wolf V, Ke G, Dharmarajan AM, Bielke W, Artuso L, Saurer S, Friis R . 1997 FEBS Lett. 417: 385–389

  • Wong GT, Avin BJ, McMahon AP . 1994 Mol. Cell. Biol. 14: 6278–6286

  • Yoshimura S, Sakai H, Ohguchi K, Nakashima S, Banno Y, Nishimura Y, Sakai N, Nozawa Y . 1997 J. Neurochem. 69: 713–720

  • Zhou Z, Wang J, Han X, Zhou J, Linder S . 1998 Int. J. Cancer 78: 95–99

  • Zinda MJ, Vlahos CJ, Lai MT . 2001 Biochem. Biophys. Res. Commun. 280: 1107–1115

Download references

Acknowledgements

We gratefully acknowledge the supply of cell lines from Drs EG Van Meir, J Kitajevski, and J Smith. This work was supported by grants from the National Institutes of Health (CA-74321), Pediatric Brain Tumor Foundation of the United States, and the Association for Research of Childhood Cancer to KS Srivenugopal and a NIH grant (CA-79644) to F Ali-Osman.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Kalkunte S Srivenugopal.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shou, J., Ali-Osman, F., Multani, A. et al. Human Dkk-1, a gene encoding a Wnt antagonist, responds to DNA damage and its overexpression sensitizes brain tumor cells to apoptosis following alkylation damage of DNA. Oncogene 21, 878–889 (2002). https://doi.org/10.1038/sj.onc.1205138

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1205138

Keywords

This article is cited by

Search

Quick links