Ku70 and poly(ADP-ribose) polymerase-1 competitively regulate β-catenin and T-cell factor-4-mediated gene transactivation:: Possible linkage of DNA damage recognition and Wnt signaling

被引:62
作者
Idogawa, Masashi
Masutani, Mitsuko
Shitashige, Miki
Honda, Kazufumi
Tokino, Takashi
Shinomura, Yasuhisa
Imai, Kohzoh
Hirohashi, Setsuo
Yamada, Tesshi
机构
[1] Natl Canc Ctr, Res Inst, Chemotherapy Div, Chuo Ku, Tokyo 1040045, Japan
[2] Natl Canc Ctr, Res Inst, ADP Ribosylat Oncol Project, Tokyo 1040045, Japan
[3] Sapporo Med Univ, Biomed Res Ctr, Canc Res Inst, Dept Mol Biol, Sapporo, Hokkaido, Japan
[4] Sapporo Med Univ, Biomed Res Ctr, Dept Internal Med 1, Sapporo, Hokkaido, Japan
[5] Sapporo Med Univ, Biomed Res Ctr, Dept Biomed Engn, Sapporo, Hokkaido, Japan
关键词
D O I
10.1158/0008-5472.CAN-06-2360
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Formation of the T-cell factor-4 (TCF-4) and beta-catenin nuclear complex is considered crucial to embryonic development and colorectal carcinogenesis. We previously reported that poly(ADP-ribose) polymerase-1 (PARP-1) interacts with the TCF-4 and beta-catenin complex and enhances its transcriptional activity. However, its biological significance remains unexplained. Using immunoprecipitation and mass spectrometry, we found that two Ku proteins, Ku70 and Ku80, were also associated with the complex. Knockdown of Ku70 by RNA interference increased the amount of beta-catenin associated with TCF-4 and enhanced the transcriptional activity. PARP-1 competed with Ku70 for binding to TCF-4. Treatment with bleomycin, a DNA-damaging alkylating agent, induced polyADP-ribosylation of PARP-1 protein and inhibited its interaction with TCF-4. Bleomycin conversely increased the amounts of Ku70 coimmunoprecipitated with TCF-4 and removed beta-catenin from TCF-4. We propose a working model in which the transcriptional activity of TCF-4 is regulated by the relative amount of Ku70, PARP-1, and beta-catenin proteins binding to TCF-4. Identification of the functional interaction of Ku70 as well as PARP-1 with the TCF-4 and beta-catenin transcriptional complex may provide insights into a novel linkage between DNA damage recognition/repair and Wnt signaling.
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页码:911 / 918
页数:8
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