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Differential roles for the coactivators CBP and p300 on TCF/β-catenin-mediated survivin gene expression

Abstract

The inhibitor of apoptosis (IAP) protein survivin is highly expressed in cancers, but not in normal differentiated tissues. TCF/β-catenin signaling has been reported to participate in the regulation of survivin transcription in colon cancer. We have recently characterized ICG-001, a small molecule specific inhibitor of the β-catenin/Creb-binding protein (CBP) interaction. Inhibition of the β-catenin/CBP interaction represses a subset of TCF/β-catenin-mediated transcription. ICG-001 potently inhibits survivin gene transcription and expression. ICG-001-mediated downregulation of survivin expression enhanced caspase-3 activity and apoptosis, which was rescued by overexpression of wild type but not mutant (C84A) survivin. Small interfering RNA and genetic reduction of CBP also decreased survivin expression. Chromatin immunoprecipitation assay confirmed that CBP is the crucial coactivator for TCF/β-catenin-mediated survivin transcription. Furthermore, ICG-001-induced recruitment of p300 to the survivin promoter led to concomitant recruitment of SUMO-1, HDAC6 and PML proteins, which have been associated with transcriptional repression. These findings demonstrate that CBP and p300 play very distinct roles in survivin gene transcription.

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Acknowledgements

We gratefully acknowledge Drs Richard Goodman (Vollum Institute, Oregon Health Science Center) and David Livingston (Dana-Farber Cancer Institute) for generous gifts of CBP and p300 expression vectors, respectively, Dr Randy Moon (Howard Hughes Medical Institute and University of Washington) for the point mutant β-catenin, Dr Feng Li (Roswell Park Cancer Research Institute) for the pLuc-6270 survivin promoter construct, Dr Vivienne Rebel (Dana-Farber Cancer Institute) for the MEF cells and Dr Todd Waldmann for the HCT116 isogenic cell lines. We thank the ChoongWae Pharma Corporation for financial support.

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Correspondence to Michael Kahn.

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Ma, H., Nguyen, C., Lee, KS. et al. Differential roles for the coactivators CBP and p300 on TCF/β-catenin-mediated survivin gene expression. Oncogene 24, 3619–3631 (2005). https://doi.org/10.1038/sj.onc.1208433

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