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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.

Publication ,  Journal Article
Shou, J; Ali-Osman, F; Multani, AS; Pathak, S; Fedi, P; Srivenugopal, KS
Published in: Oncogene
January 31, 2002

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, H(2)O(2) 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.

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Published In

Oncogene

DOI

ISSN

0950-9232

Publication Date

January 31, 2002

Volume

21

Issue

6

Start / End Page

878 / 889

Location

England

Related Subject Headings

  • bcl-2-Associated X Protein
  • Zebrafish Proteins
  • Wnt Proteins
  • Ultraviolet Rays
  • Tumor Suppressor Protein p53
  • Tumor Cells, Cultured
  • Transfection
  • Telomere
  • Sphingosine
  • Signal Transduction
 

Citation

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MLA
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Shou, J., Ali-Osman, F., Multani, A. S., Pathak, S., Fedi, P., & Srivenugopal, K. S. (2002). 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(6), 878–889. https://doi.org/10.1038/sj.onc.1205138
Shou, Jiang, Francis Ali-Osman, Asha S. Multani, Sen Pathak, Paolo Fedi, and Kalkunte S. Srivenugopal. “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, no. 6 (January 31, 2002): 878–89. https://doi.org/10.1038/sj.onc.1205138.

Published In

Oncogene

DOI

ISSN

0950-9232

Publication Date

January 31, 2002

Volume

21

Issue

6

Start / End Page

878 / 889

Location

England

Related Subject Headings

  • bcl-2-Associated X Protein
  • Zebrafish Proteins
  • Wnt Proteins
  • Ultraviolet Rays
  • Tumor Suppressor Protein p53
  • Tumor Cells, Cultured
  • Transfection
  • Telomere
  • Sphingosine
  • Signal Transduction