RRC ID 73330
Author Idogawa M, Yamada T, Honda K, Sato S, Imai K, Hirohashi S.
Title Poly(ADP-ribose) polymerase-1 is a component of the oncogenic T-cell factor-4/beta-catenin complex.
Journal Gastroenterology
Abstract BACKGROUND & AIMS:T-cell factor (TCF)-4 regulates a certain set of genes related to growth and differentiation of intestinal epithelial cells. Aberrant transactivation of these TCF-4-regulated genes by beta-catenin protein plays a crucial role in early intestinal carcinogenesis, and the transcriptional machinery of the TCF-4/beta-catenin complex is likely to contain targets for molecular therapy. We explored the molecular composition of the TCF-4/beta-catenin transcriptional complex by means of proteomics.
METHODS & RESULTS:A protein of approximately 112 kilodaltons was consistently coimmunoprecipitated with FLAG-tagged TCF-4 transiently expressed in HEK293 cells, and the protein was identified by mass spectrometry as poly(ADP-ribose) polymerase-1 (PARP-1). PARP-1 physically interacted with TCF-4 and augmented the transcriptional activity of the beta-catenin/TCF-4 complex. Knockdown of PARP-1 by RNA interference significantly suppressed both transcriptional activity and proliferation by colorectal cancer cells. Auto-polyADP-ribosylation of the PARP-1 protein induced by DNA damage inhibited the functional interaction of PARP-1 with TCF-4. PARP-1 was overexpressed in the intestinal adenomas of patients with familial adenomatous polyposis and multiple intestinal polyposis mice. The expression of PARP-1 was closely associated with the accumulation of beta-catenin and with the undifferentiated status of intestinal epithelial cells.
CONCLUSIONS:In this study, we identified PARP-1 as a novel coactivator of the beta-catenin/TCF-4 complex. Although PARP-1 has been believed to play a protective role against carcinogenesis, these expression patterns and functional properties of PARP-1 were highly suggestive of its participation in early colorectal carcinogenesis.
Volume 128(7)
Pages 1919-36
Published 2005-6-1
DOI 10.1053/j.gastro.2005.03.007
PII S0016508505003884
PMID 15940627
MeSH Cell Transformation, Neoplastic / genetics Colorectal Neoplasms / genetics* Colorectal Neoplasms / pathology Cytoskeletal Proteins / biosynthesis Cytoskeletal Proteins / genetics* DNA-Binding Proteins / biosynthesis DNA-Binding Proteins / physiology* Gene Expression Regulation* Humans Poly (ADP-Ribose) Polymerase-1 Poly(ADP-ribose) Polymerases / biosynthesis Poly(ADP-ribose) Polymerases / physiology* Proteomics RNA Interference Reverse Transcriptase Polymerase Chain Reaction TCF Transcription Factors Trans-Activators / biosynthesis Trans-Activators / genetics* Transcription Factor 7-Like 2 Protein Transcription Factors / biosynthesis Transcription Factors / physiology* Transcription, Genetic* Tumor Cells, Cultured beta Catenin
IF 17.373
Human and Animal Cells 293(RCB1637)