RRC ID 42882
Author Idogawa M, Masutani M, Shitashige M, Honda K, Tokino T, Shinomura Y, Imai K, Hirohashi S, Yamada T.
Title Ku70 and poly(ADP-ribose) polymerase-1 competitively regulate beta-catenin and T-cell factor-4-mediated gene transactivation: possible linkage of DNA damage recognition and Wnt signaling.
Journal Cancer Res
Abstract 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.
Volume 67(3)
Pages 911-8
Published 2007-2-1
DOI 10.1158/0008-5472.CAN-06-2360
PII 67/3/911
PMID 17283121
MeSH Animals Antigens, Nuclear / genetics Antigens, Nuclear / metabolism* Cell Line Cell Nucleus / genetics Cell Nucleus / metabolism DNA Damage / physiology* DNA-Binding Proteins / genetics DNA-Binding Proteins / metabolism* HCT116 Cells Humans Ku Autoantigen Mice Mice, Knockout Poly (ADP-Ribose) Polymerase-1 Poly(ADP-ribose) Polymerases / metabolism* Protein Binding Protein Structure, Tertiary Signal Transduction TCF Transcription Factors / antagonists & inhibitors TCF Transcription Factors / genetics TCF Transcription Factors / metabolism* Transcription Factor 7-Like 2 Protein Transcriptional Activation Transfection Wnt Proteins / metabolism* beta Catenin / antagonists & inhibitors beta Catenin / genetics beta Catenin / metabolism*
IF 8.378
Times Cited 55
Human and Animal Cells