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.
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.
Shou
Jiang
J
Department of Neurosurgery, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Road, Houston, TX 77030, USA.
Ali-Osman
Francis
F
Multani
Asha S
AS
Pathak
Sen
S
Fedi
Paolo
P
Srivenugopal
Kalkunte S
KS
D000478:Alkylation; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019254:Genes, bcl-2; D016158:Genes, p53; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D015398:Signal Transduction / Q000502:physiology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D016615:Telomere / Q000187:drug effects / Q000648:ultrastructure; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000378:metabolism / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000502:physiology*; D014466:Ultraviolet Rays; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051028:bcl-2-Associated X Protein
D018906:Antineoplastic Agents, Alkylating; C494826:BAX protein, human; C501126:DKK1 protein, human; D004273:DNA, Neoplasm; D036341:Intercellular Signaling Peptides and Proteins; C064769:N-acetylsphingosine; D009363:Neoplasm Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D016159:Tumor Suppressor Protein p53; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051028:bcl-2-Associated X Protein; C501128:dkk1b protein, zebrafish; D006861:Hydrogen Peroxide; D013110:Sphingosine