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

被引:76
作者
Shou, J
Ali-Osman, F
Multani, AS
Pathak, S
Fedi, P
Srivenugopal, KS
机构
[1] Univ Texas, MD Anderson Canc Ctr, Dept Neurosurg, Houston, TX 77030 USA
[2] Univ Texas, MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA
[3] CUNY Mt Sinai Sch Med, Derald H Ruttenberg Canc Ctr, New York, NY 10029 USA
关键词
Wnt antagonist; apoptosis; p53; alkylating agents; brain tumors;
D O I
10.1038/sj/onc/1205138
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 glioblastorna 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.
引用
收藏
页码:878 / 889
页数:12
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